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{{Short description|Amino acid active in mitochondria}} |
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{{cs1 config|name-list-style=vanc}} |
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{{drugbox |
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{{drugbox |
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| Verifiedfields = changed |
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| verifiedrevid = 443500697 |
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| Watchedfields = changed |
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| IUPAC_name = 3-hydroxy-4-(trimethylazaniumyl)butanoate |
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| verifiedrevid = 460019989 |
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| image = Carnitine structure.png |
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| drug_name = |
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| width = 202 |
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| type = |
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| IUPAC_name = 3-hydroxy-4-(trimethylazaniumyl)butanoate |
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| image = Carnitine.svg |
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| width = 180 |
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| alt = |
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| caption = |
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| image2 = Carnitine-3D-structure.png |
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<!--Clinical data--> |
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<!--Clinical data-->| Drugs.com = {{drugs.com|CONS|carnitine}} |
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| MedlinePlus = |
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| Drugs.com = {{drugs.com|CONS|carnitine}} |
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| licence_EU = |
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| pregnancy_category = |
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| licence_US = |
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| legal_status = |
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| pregnancy_AU = |
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| routes_of_administration = oral and iv |
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| pregnancy_US = B |
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| pregnancy_category = |
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| legal_US = OTC |
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| legal_status = |
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| routes_of_administration = ], ] |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data-->| bioavailability = <10% |
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| protein_bound = None |
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| bioavailability = < 10% |
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| metabolism = slightly {{Clarify|date=September 2019}} |
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| protein_bound = None |
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| elimination_half-life = |
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| metabolism = slightly |
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| excretion = Urine (>95%) |
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| elimination_half-life = |
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| excretion = Urine (> 95%) |
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<!--Identifiers--> |
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<!--Identifiers-->| index2_label = ''R''-(-)- |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 406-76-8 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number2_Ref = {{cascite|correct|CAS}} |
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| CAS_number = 541-15-1 |
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| CAS_number2 = 541-15-1 |
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| ATC_prefix = A16 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| ATC_suffix = AA01 |
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| UNII = S7UI8SM58A |
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| ATC_supplemental = |
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| UNII2_Ref = {{fdacite|correct|FDA}} |
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| PubChem = 288 |
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| UNII2 = 0G389FZZ9M |
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| DrugBank_Ref = {{drugbankcite|correct|drugbank}} |
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| ATC_prefix = A16 |
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| DrugBank = <!-- blanked - oldvalue: APRD01070 --> |
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| ATC_suffix = AA01 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ATC_supplemental = ({{sm|l}}-form) |
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| ChemSpiderID = 282 |
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| PubChem = 288 |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| DrugBank_Ref = {{drugbankcite|changed|drugbank}} |
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| UNII = 0G389FZZ9M |
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| DrugBank = DB00583 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| KEGG = C00318 |
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| ChemSpiderID = 282 |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| ChEBI = 17126 |
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| KEGG = C00318 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 172513 |
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| ChEBI = 17126 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 172513 |
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<!--Chemical data--> |
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<!--Chemical data-->| C = 7 |
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| C=7 | H=15 | N=1 | O=3 |
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| H = 15 |
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| N = 1 |
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| molecular_weight = 161.199 g/mol |
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| O = 3 |
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| smiles = C(C)(C)CC(CC(=O))O |
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| smiles = C(C)(C)CC(CC(=O))O |
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| InChI = 1/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3 |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3 |
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| StdInChI = 1S/C7H15NO3/c1-8(2,3)5-6(9)4-7(10)11/h6,9H,4-5H2,1-3H3 |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChIKey = PHIQHXFUZVPYII-UHFFFAOYSA-N |
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| StdInChIKey = PHIQHXFUZVPYII-UHFFFAOYSA-N |
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}} |
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}} |
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: ''Carnitine should not be confused with ]''. |
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'''Carnitine''' is a ] involved in ] in most mammals, plants, and some bacteria.<ref name="lpi">{{cite web|url=https://lpi.oregonstate.edu/mic/dietary-factors/L-carnitine|title=L-Carnitine|date=2019-12-01|publisher=Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR|access-date=2020-04-29|archive-date=2020-11-26|archive-url=https://web.archive.org/web/20201126195452/https://lpi.oregonstate.edu/mic/dietary-factors/L-carnitine|url-status=live}}</ref><ref name="pmid6361812">{{cite journal | vauthors = Bremer J | title = Carnitine--metabolism and functions | journal = Physiological Reviews | volume = 63 | issue = 4 | pages = 1420–80 | date = October 1983 | pmid = 6361812 | doi = 10.1152/physrev.1983.63.4.1420 }}</ref><ref name="ods">{{cite web|url=https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/|title=Carnitine|publisher=Office of Dietary Supplements, US National Institutes of Health|date=2017-10-10|access-date=2020-04-29|archive-date=2020-11-24|archive-url=https://web.archive.org/web/20201124063904/https://ods.od.nih.gov/factsheets/Carnitine-HealthProfessional/|url-status=live}}</ref><ref name="Drugs.com-2020-Uses-Benefits-Dosage">{{cite web|url=https://www.drugs.com/npp/l-carnitine.html|title=L-carnitine: Uses, benefits and dosage|publisher=Drugs.com|date=2020-01-20|access-date=2020-04-29|archive-date=2020-10-31|archive-url=https://web.archive.org/web/20201031050102/https://www.drugs.com/npp/l-carnitine.html|url-status=live}}</ref> In support of energy metabolism, carnitine transports ] from the cytosol into ] to be ] for free energy production, and also participates in removing products of metabolism from cells.<ref name=ods/> Given its key metabolic roles, carnitine is concentrated in tissues like ] and ] that metabolize fatty acids as an energy source.<ref name=ods/> Generally individuals, including strict ], synthesize enough L-carnitine ].<ref name=lpi/> |
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'''Carnitine''' is a ] biosynthesized from the ] ] and ].<ref>{{cite journal |author=Steiber A, Kerner J, Hoppel C |title=Carnitine: a nutritional, biosynthetic, and functional perspective |journal=Mol. Aspects Med. |volume=25 |issue=5-6 |pages=455–73 |year=2004 |pmid=15363636 |doi=10.1016/j.mam.2004.06.006}}</ref> In living cells, it is required for the transport of ]s from the ] into the ] during the breakdown of ]s (fats) for the generation of metabolic energy. It is widely available as a ]. Carnitine was originally found as a ] for ] and labeled ''vitamin Bt''. Carnitine exists in two ]s: Its biologically active form is <small>L</small>-carnitine, whereas its ], ''<small>D</small>-carnitine'', is biologically inactive.<ref>{{cite journal| title=Metabolic and mechanical effects using L- and D-carnitine in working swine hearts| author=A. J. Liedtke, S. H. Nellis, L. F. Whitesell and C. Q. Mahar | journal=Heart and Circulatory Physiology| volume=243 | pages= H691–H697| date=1 November 1982| url=http://ajpheart.physiology.org/cgi/content/abstract/243/5/H691| issue=5| pmid=7137362}}</ref> |
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Carnitine exists as one of two ]s: the two ]s {{sm|d}}-carnitine (''S''-(+)-) and {{sm|l}}-carnitine (''R''-(−)-).<ref name="pubchem">{{cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/10917|title=Levocarnitine|publisher=PubChem, National Library of Medicine, US National Institutes of Health|date=2020-04-25|access-date=2020-04-29|archive-date=2020-08-07|archive-url=https://web.archive.org/web/20200807133624/https://pubchem.ncbi.nlm.nih.gov/compound/10917|url-status=live}}</ref> Both are biologically active, but only {{sm|l}}-carnitine naturally occurs in animals, and {{sm|d}}-carnitine is toxic as it inhibits the activity of the {{sm|l}}-form.<ref name="pmid8347126">{{cite journal | vauthors = Matsuoka M, Igisu H | title = Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia | journal = Biochemical Pharmacology | volume = 46 | issue = 1 | pages = 159–64 | date = July 1993 | pmid = 8347126 | doi = 10.1016/0006-2952(93)90360-9 }}</ref> At room temperature, pure carnitine is a whiteish powder, and a water-soluble ] with relatively low toxicity. Derived from amino acids,<ref name="pmid4786530">{{cite journal | vauthors = Cox RA, Hoppel CL | title = Biosynthesis of carnitine and 4-N-trimethylaminobutyrate from 6-N-trimethyl-lysine | journal = The Biochemical Journal | volume = 136 | issue = 4 | pages = 1083–90 | date = December 1973 | pmid = 4786530 | pmc = 1166060 | doi = 10.1042/bj1361083 }}</ref> carnitine was first ]ed from meat extracts in 1905, leading to its name from Latin, "''caro/carnis''" or flesh.<ref name="pmid6361812"/> |
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==Biochemistry== |
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===Biosynthesis=== |
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In animals, carnitine is biosynthesized primarily in the ] and ]s from the amino acids ] (via ]) or ].<ref>{{cite web |url=http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/lca_0060.shtml |title=L-Carnitine |accessdate=2007-06-01 |work= |archiveurl = http://web.archive.org/web/20070508224849/http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/lca_0060.shtml <!-- Bot retrieved archive --> |archivedate = 2007-05-08}}</ref> ] (]) is essential to the synthesis of carnitine. During ]<ref>Cederblad, G; Niklasson, A; Rydgren, B; Albertsson-Wikland, K; Olegård, R; “Carnitine in Maternal and Neonatal Plasma”; Acta Pædiatrica; Published Online: 21 Jan 2008; Volume 74, Issue 4: Pp 500 – 504</ref> or ],<ref>Cederblad, G; Fahraeus, L; Lindgren, K; “Plasma carnitine and renal-carnitine clearance during pregnancy”; American Journal of Clinical Nutrition; 1986; Volume 44:Pp</ref> the requirement of carnitine might exceed its natural production. |
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Some individuals with ] or medical disorders (such as preterm infants) cannot make enough carnitine, requiring dietary supplementation.<ref name=lpi/><ref name=ods/><ref name="Drugs.com-2020-Uses-Benefits-Dosage"/> Despite common carnitine supplement consumption among ]s for improved exercise performance or recovery, there is insufficient ] to indicate it provides any benefit.<ref name=ods/><ref name="Drugs.com-2020-Uses-Benefits-Dosage"/> |
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=== Role in fatty acid metabolism === |
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Carnitine transports long-chain acyl groups from fatty acids into the ], so they can be broken down through ] to ] to obtain usable energy via the ]. In some organisms such as fungi, the acetate is used in the ] for ] and formation of ]s. Fatty acids must be activated before binding to the carnitine molecule to form ''acylcarnitine''. The free fatty acid in the cytosol is attached with a ] bond to ] (CoA). This reaction is catalyzed by the enzyme ] and driven to completion by ]. |
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== Biological role == |
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The acyl group on CoA can now be transferred to carnitine and the resulting acylcarnitine transported into the ]. This occurs via a series of similar steps: |
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The primary biological functions of carnitine in humans include the following:<ref name="pmid32958033">{{cite journal |vauthors=Sawicka AK, Renzi G, Olek RA |title=The bright and the dark sides of L-carnitine supplementation: a systematic review |journal=J Int Soc Sports Nutr |volume=17 |issue=1 |pages=49 |date=September 2020 |pmid=32958033 |pmc=7507632 |doi=10.1186/s12970-020-00377-2|doi-access=free }}</ref> |
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* ] transport across the ] by forming long-chain acylcarnitine esters which are shuttled into the mitochondria, where they undergo ] to produce ], the cell's main energy currency;<ref name="pmid32958033"/> |
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* ] and ] stabilization by transferring ]s for maintaining metabolic flexibility and energy production, particularly during fasting or exercise;<ref name="pmid32958033"/> |
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* detoxification of ]s by forming acylcarnitine, which is then excreted to prevent the accumulation of potentially toxic fatty acyl intermediates;<ref name="pmid32958033"/> |
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* regulation of cellular metabolism by participating in the conversion and utilization of different fuel sources, enabling cells to switch between ] and fatty acid metabolism as needed;<ref name="pmid32958033"/> |
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* ] action to protect cells from ] (caused by ] toxicity) and damage.<ref name="pmid32958033"/> |
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== Biochemistry == |
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# Acyl CoA is conjugated to carnitine by ] (palmitoyltransferase) located on the outer mitochondrial membrane |
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=== Chemical properties === |
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# Acylcarnitine is shuttled inside by a ] |
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Carnitine is a ], meaning it has both positive and negative charges in its structure. In an aqueous solution, L-carnitine is freely soluble and its ionizable groups, COO<sup>-</sup> and N<sup>+</sup>(CH<sub>3</sub>)<sub>3</sub>, are over 90% ] at physiological pH (~7.4) for humans.<ref>{{cite journal|journal=Lohman Information|issue=27|volume=15-21|year=2002|title=The physiological role of L-carnitine|vauthors=Harmeyer J|url=https://www.lohmann-information.com/content/l_i_27_article_3.pdf}}</ref> |
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# Acylcarnitine is converted to acyl CoA by ] (palmitoyltransferase) located on the inner mitochondrial membrane. The liberated carnitine returns to the cytosol. |
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=== Biosynthesis and metabolism === |
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Human genetic disorders such as ], ], ] and ] affect different steps of this process.<ref>{{cite journal |author=Olpin S |title=Fatty acid oxidation defects as a cause of neuromyopathic disease in infants and adults |journal=Clin. Lab. |volume=51 |issue=5-6 |pages=289–306 |year=2005 |pmid=15991803}}</ref> |
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==== Physiological effects in humans ==== |
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As an example of normal biosynthesis of carnitine in humans, a {{convert|70|kg|lb|adj=on}} person would produce 11–34 mg of carnitine per day.<ref name=lpi/> Adults eating mixed diets of ] and other ]s ingest some 60–180 mg of carnitine per day, while vegans consume about 10–12 mg per day.<ref name=ods/> Most (54–86%) carnitine obtained from the diet is absorbed in the ] before entering the blood.<ref name=ods/> The total body content of carnitine is about {{convert|20|g}} in a person weighing {{convert|70|kg}}, with nearly all of it contained within skeletal muscle cells.<ref name=ods/> Carnitine metabolizes at rates of about 400 μmol (65mg) per day, an amount less than 1% of total body stores.<ref name=lpi/> |
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==== Biosynthesis in eukaryotes ==== |
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Carnitine acyltransferase I undergoes ] inhibition as a result of ], an intermediate in fatty acid biosynthesis, to prevent futile cycling between β-oxidation and ]. |
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{{Main|carnitine biosynthesis}} |
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] |
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Many ]s have the ability to synthesize carnitine, including humans.<ref name=lpi/><ref name=ods/> Humans synthesize carnitine from the substrate ] (6-''N''-trimethyllysine), which is in turn derived from the ] of the amino acid ].<ref name=lpi/> TML is then hydroxylated into hydroxytrimethyllysine (HTML) by ] (TMLD), requiring the presence of ] and iron. HTML is then cleaved by HTML aldolase (HTMLA, a ] requiring enzyme), yielding 4-trimethylaminobutyraldehyde (TMABA) and ]. TMABA is then ] into gamma-butyrobetaine in an NAD<sup>+</sup>-dependent reaction, catalyzed by TMABA dehydrogenase.<ref name=lpi/> Gamma-butyrobetaine is then hydroxylated by ] (a ] binding enzyme<ref name="pmid20599753">{{cite journal | vauthors = Tars K, Rumnieks J, Zeltins A, Kazaks A, Kotelovica S, Leonciks A, Sharipo J, Viksna A, Kuka J, Liepinsh E, Dambrova M | display-authors = 6 | title = Crystal structure of human gamma-butyrobetaine hydroxylase | journal = Biochemical and Biophysical Research Communications | volume = 398 | issue = 4 | pages = 634–9 | date = August 2010 | pmid = 20599753 | doi = 10.1016/j.bbrc.2010.06.121 }}</ref>) into {{sm|l}}-carnitine, requiring iron in the form of ].<ref name=lpi/><ref name="pmid20306513">{{cite journal | vauthors = Strijbis K, Vaz FM, Distel B | title = Enzymology of the carnitine biosynthesis pathway | journal = IUBMB Life | volume = 62 | issue = 5 | pages = 357–62 | date = May 2010 | pmid = 20306513 | doi = 10.1002/iub.323 | doi-access = }}</ref> |
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==== Fatty acid transport ==== |
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==Physiological effects== |
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Carnitine is involved in transporting fatty acids across the mitochondrial membrane, by forming a long chain acetylcarnitine ester and being transported by ] and ].<ref name="pmid20398344">{{cite journal | vauthors = Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q | title = Role of carnitine in disease | journal = Nutrition & Metabolism | volume = 7 | pages = 30 | date = April 2010 | pmid = 20398344 | pmc = 2861661 | doi = 10.1186/1743-7075-7-30 | doi-access = free }}</ref> |
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===Effects on bone mass=== |
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In the course of human aging, carnitine concentration in cells diminishes, affecting fatty acid metabolism in various tissues. Particularly adversely affected are bones, which require continuous reconstructive and metabolic functions of osteoblasts for maintenance of bone mass. |
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==== Acetyl-CoA stabilization ==== |
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There is a close correlation between changes in plasma levels of ] and ] activity and a reduction in osteocalcin plasma levels is an indicator of reduced osteoblast activity,<ref>Claudio Cavazza, ''Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome'' (2002), US Patent 6,335,038, column 4.</ref> which appears to underlie ] in elderly subjects and in postmenopausal women. Administration of a carnitine mixture or ] is capable of increasing serum osteocalcin concentrations of animals thus treated, whereas serum osteocalcin levels tend to decrease with age in control animals.<ref>Claudio Cavazza, ''Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome'' (2002), US Patent 6,335,038, columns 3-4.</ref> |
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Carnitine plays a role in stabilizing ] and ] levels through the ability to receive or give an acetyl group.<ref name=lpi/> |
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==== Tissue distribution of carnitine-biosynthetic enzymes in humans ==== |
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===Antioxidant effects=== |
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The tissue distribution of carnitine-biosynthetic enzymes in humans indicates TMLD to be active in the liver, heart, muscle, brain and highest in the kidneys.<ref name=lpi/> HTMLA activity is found primarily in the liver. The rate of TMABA oxidation is greatest in the liver, with considerable activity also in the kidneys.<ref name=lpi/> |
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The carnitines exert a substantial ] action, thereby providing a protective effect against ] of phospholipid membranes and against ] induced at the myocardial and endothelial cell level.<ref>Claudio Cavazza, ''Composition for the Prevention and Treatment of Osteoporosis due to Menopause Syndrome'' (2002), US Patent 6,335,038, column 3.</ref> |
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=== Carnitine shuttle system === |
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==Potential uses as a pharmaceutical== |
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The free-floating ]s, released from ]s to the blood, bind to carrier protein molecule known as ] that carry the fatty acids to the ] of target cells such as the heart, skeletal muscle, and other tissue cells, where they are used for fuel. Before the target cells can use the fatty acids for ATP production and ], the fatty acids with chain lengths of 14 or more carbons must be activated and subsequently transported into ] of the cells in three enzymatic reactions of the carnitine shuttle'''.'''<ref name="Nelson-2017">{{cite book | vauthors = Nelson DL, Cox MM, Lehninger AL | date = 2017 | title = Lehninger principles of biochemistry | edition = 7th | location = New York, NY | publisher = W.H. Freeman and Company | isbn = 978-1-4641-2611-6}}</ref> |
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===Heart conditions=== |
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Carnitine is primarily used for heart-related conditions. Several clinical trials show that L-carnitine and propionyl-L-carnitine can be used along with conventional treatment for angina to reduce medication needs and improve the ability of those with angina to exercise without chest pain.<ref>{{cite journal |author=Cacciatore L, Cerio R, Ciarimboli M, Cocozza M, Coto V, D'Alessandro A, D'Alessandro L, Grattarola G, Imparato L, Lingetti M |title = The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. |journal = Drugs Exp Clin Res |volume = 17 |issue = 4 |pages = 225–235 |year = 1991 |pmid = 1794297}}</ref><ref>{{cite journal |author= Bartels GL, Remme WJ, Pillay M, et al. |title = Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris |journal = The American Journal of Cardiology |volume = 74 |issue = 2 |pages = 125–130 |year = 1994 |month = July |doi = 10.1016/0002-9149(94)90084-1 |pmid= 8023775 }}</ref> |
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There is little evidence about a positive effect of the use of carnitine after a heart attack. Some studies suggest that people taking L-carnitine may be less likely to suffer a subsequent heart attack or experience chest pain and abnormal heart rhythms.<ref>{{cite journal |author= Michael A. Arsenian|title = Carnitine and its derivatives in cardiovascular disease|journal = Progress in Cardiovascular Diseases|volume = 40 |issue = 3 |pages = 265–286|year = 1997 |month = November - December |doi = 10.1016/S0033-0620(97)80037-0 |pmid= 9406679 }}</ref> However, other studies have not found similar benefits.<ref>{{cite journal |unused_data= supplement 1 |author= Kamyar Kalantar-Zadeh, MPHa, Stefan D. Anker, Tamara B. Horwich and Gregg C. Fonarow |title = Nutritional and Anti-Inflammatory Interventions in Chronic Heart Failure |journal = The American Journal of Cardiology|volume = 101 |issue = 11 |pages = S89–S103|year = 2008 |month = June |doi = 10.1016/j.amjcard.2008.03.007 |pmid= 18514634}}</ref> Further research on this subject is needed. |
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The first reaction of the carnitine shuttle is a two-step process catalyzed by a family of ]s of acyl-CoA synthetase that are found in the outer mitochondrial membrane''',''' where they promote the activation of fatty acids by forming a ] bond between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl–CoA.<ref name="Nelson-2017" /> |
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===Kidney disease and dialysis=== |
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Because kidneys produce carnitine, kidney disease may lead to the deficiency of carnitine in the body. Thus, carnitine may be prescribed to those with kidney disease.<ref>{{cite journal |author= Wei Huang, Sobia N. Shaikh, Malliga E. Ganapathy, Ullrich Hopfer, Frederick H. Leibach, A. Lee Carter and Vadivel Ganapathy |title = Carnitine transport and its inhibition by sulfonylureas in human kidney proximal tubular epithelial cells |journal = Biochemical Pharmacology|volume = 58 |issue = 8 |pages = 1361–1370 |year = 1999 |month = October |doi = 10.1016/S0006-2952(99)00219-1 |pmid= 10487540 }}</ref> |
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In the first step of the reaction, acyl-CoA synthetase catalyzes the transfer of ] group (AMP) from an ATP molecule onto the fatty acid generating a fatty acyl–adenylate intermediate and a pyrophosphate group (PP<sub>i</sub>). The ], formed from the hydrolysis of the two high-energy bonds in ATP, is immediately hydrolyzed to two molecules of P<sub>i</sub> by inorganic pyrophosphatase. This reaction is highly exergonic which drives the activation reaction forward and makes it more favorable. In the second step, the ] of a cytosolic ] attacks the acyl-adenylate, displacing AMP to form thioester fatty acyl-CoA.<ref name="Nelson-2017" /> |
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===Effect in male infertility=== |
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The use of carnitine showed some promise in a controlled trial in selected cases of ] by improving sperm quality.<ref>{{cite journal| author=Lenzi A, Lombardo F, Sgro P, Salacone P, Caponecchia L, Dondero F, Gandini L |title=Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. |journal=Fertility and Sterility (2003), Volume 79 , Issue 2 , Pages 292 - 300 |pmid=12568837| year=2003| volume=79| issue=2| pages=292–300}}</ref> L-carnitine supplementation has also shown to have beneficial effects in the treatment of ], a major cause of male infertility. <ref>{{cite journal |author=Seo JT, Kim KT, Moon MH, Kim WT |title=The significance of microsurgical varicocelectomy in the treatment of subclinical varicocele |journal=Fertil. Steril. |volume=93 |issue=6 |pages=1907–10 |year=2010 |month=April |pmid=19249033 |doi=10.1016/j.fertnstert.2008.12.118 |url=}}</ref> |
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In the second reaction, acyl-CoA is transiently attached to the hydroxyl group of carnitine to form fatty acylcarnitine. This transesterification is catalyzed by an enzyme found in the outer membrane of the mitochondria known as carnitine acyltransferase 1 (also called carnitine palmitoyltransferase 1, CPT1).<ref name="Nelson-2017" /> |
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===As a weight loss supplement=== |
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"Although L-carnitine has been marketed as a weight-loss supplement, there is no scientific evidence to show that it improves weight loss; however, some studies show that oral carnitine reduces fat mass, increases muscle mass, and reduces fatigue. All of these effects may contribute to weight loss."<ref></ref> Furthermore, whereas researchers in the 20th century failed to show that muscle carnitine content could be increased by dietary supplementation, this may have been in part due to inadequate lengths of the supplementation periods.<ref name="pmid21486835">{{cite journal |author=Sahlin K |title=Boosting fat burning with carnitine: an old friend comes out from the shadow |journal=J Physiol |volume=589 |issue=7 |pages=1509-10 |year=2010 |pmid=21486835}}</ref> In 2011, researchers using L-carnitine L-tartrate supplementation for 6 months in a well controlled study demonstrated not only increased muscle carnitine in subjects without carnitine deficiencies, but also an impact on muscle metabolism and performance; however, measurements of lipid oxidation were not taken in this study, and further research is needed.<ref name="pmid21224234">{{cite journal |author=Wall BT, Stephens FB, Constantin-Teodosiu D, Marimuthu K, Macdonald IA, Greenhaff PL |title=Chronic oral ingestion of L-carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans |journal=J Physiol |volume=589 |issue=4 |pages=963-73 |year=2011 |pmid=21224234}}</ref> |
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The fatty acylcarnitine ester formed then diffuses across the intermembrane space and enters the matrix by ] through ] (CACT) located on the inner mitochondrial membrane. This ] returns one molecule of carnitine from the matrix to the ] for every one molecule of fatty acyl–carnitine that moves into the matrix.<ref name="Nelson-2017" /> |
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Regular supplements of <small>L</small>-carnitine, however, contribute to energy metabolism and improved neurotransmitter function in the brain in elderly patients.<ref>Mariano Malaguarnera, Lisa Cammalleri, Maria Pia Gargante, Marco Vacante, Valentina Colonna and Massimo Motta: "L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial", American Journal of Clinical Nutrition, Volume 86, No. 6, 1738-1744, December 2007</ref> |
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In the third and final reaction of the carnitine shuttle, the fatty acyl group is transferred from fatty acyl-carnitine to coenzyme A, regenerating fatty acyl–CoA and a free carnitine molecule. This reaction takes place in the mitochondrial matrix and is catalyzed by carnitine acyltransferase 2 (also called carnitine palmitoyltransferase 2, CPT2), which is located on the inner face of the inner mitochondrial membrane. The carnitine molecule formed is then shuttled back into the intermembrane space by the same cotransporter (CACT) while the fatty acyl-CoA enters ].<ref name="Nelson-2017" /> |
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===As an antidote in ] poisoning=== |
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" L-carnitine supplementation ...is thought to provide benefit, particularly in patients with concomitant hyperammonemia, encephalopathy, and/or hepatotoxicity."<ref>{{cite web | url = http://emedicine.medscape.com/article/819315-treatment | title = Toxicity, Valproate: Treatment & Medication }}</ref> Further trials are warranted, as benefit is largely theoretical, rather than proven at this stage. |
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=== Regulation of fatty acid β oxidation === |
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== Sources == |
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===Food=== |
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==== Balance ==== |
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The carnitine-mediated entry process is a rate-limiting factor for fatty acid oxidation and is an important point of regulation.<ref name="Nelson-2017" /> |
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==== Inhibition ==== |
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The highest concentrations of carnitine are found in ] and dairy products. Other natural sources of carnitine include ] and ]s (e.g. ], ], ]), ]s or ] (]s, ]s, ]s, ]s), ] (], ], ], ], ], ], ], ], ], ], ]), ]s (]s, ]s), ]s (], ], ], ], rice ], ], ], wheat ], ]) and other "health" foods (], ], ]). {{Citation needed|date=May 2008}} |
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The liver starts actively making ]s from excess glucose when it is supplied with glucose that cannot be oxidized or stored as glycogen. This increases the concentration of ], the first intermediate in fatty acid synthesis, leading to the inhibition of carnitine acyltransferase 1, thereby preventing fatty acid entry into the mitochondrial matrix for ]. This inhibition prevents fatty acid breakdown while synthesis occurs.<ref name="Nelson-2017" /> |
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==== Activation ==== |
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Carnitine shuttle activation occurs due to a need for fatty acid oxidation which is required for energy production. During vigorous muscle contraction or during fasting, ATP concentration decreases and AMP concentration increases leading to the activation of ] (AMPK). AMPK ] ], which normally catalyzes malonyl-CoA synthesis. This phosphorylation inhibits acetyl-CoA carboxylase, which in turn lowers the concentration of malonyl-CoA. Lower levels of malonyl-CoA disinhibit carnitine acyltransferase 1, allowing fatty acid import to the mitochondria, ultimately replenishing the supply of ].<ref name="Nelson-2017" /> |
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=== Transcription factors === |
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] (PPAR''α'') is a nuclear receptor that functions as a ]. It acts in muscle, adipose tissue, and liver to turn on a set of genes essential for fatty acid oxidation, including the fatty acid transporters carnitine acyltransferases 1 and 2, the fatty acyl–CoA dehydrogenases for short, medium, long, and very long acyl chains, and related enzymes.<ref name="Nelson-2017" /> |
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PPAR''α'' functions as a transcription factor in two cases; as mentioned before when there is an increased demand for energy from fat catabolism, such as during a fast between meals or long-term starvation. Besides that, the transition from fetal to neonatal metabolism in the heart. In the fetus, fuel sources in the heart muscle are glucose and lactate, but in the neonatal heart, fatty acids are the main fuel that require the PPAR''α'' to be activated so it is able in turn to activate the genes essential for ] metabolism in this stage.<ref name="Nelson-2017" /> |
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=== Metabolic defects of fatty acid oxidation === |
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More than 20 human genetic defects in ] transport or ] have been identified. In case of ] defects, acyl-carnitines accumulate in mitochondria and are transferred into the cytosol, and then into the blood. Plasma levels of acylcarnitine in newborn infants can be detected in a small blood sample by ].<ref name="Nelson-2017" /> |
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When ''β'' oxidation is defective because of either ] or deficiency in carnitine, the ω (omega) oxidation of fatty acids becomes more important in mammals. The ω oxidation of fatty acids is another pathway for F-A degradation in some species of vertebrates and mammals that occurs in the endoplasmic reticulum of the liver and kidney, it is the oxidation of the ω carbon—the carbon farthest from the carboxyl group (in contrast to <math>\beta</math> oxidation which occurs at the carboxyl end of ], in the mitochondria).<ref name=lpi/><ref name="Nelson-2017" /> |
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==Deficiency== |
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{{see|Systemic primary carnitine deficiency}} |
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Carnitine deficiency is rare in healthy people without metabolic disorders, indicating that most people have normal, adequate levels of carnitine normally produced through fatty acid metabolism.<ref name=lpi/> One study found that ] showed no signs of carnitine deficiency.<ref name="pmid2756917" /> Infants, especially ], have low stores of carnitine, necessitating use of ] ]s as a replacement for ], if necessary.<ref name=lpi/> |
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Two types of carnitine deficiency states exist. Primary carnitine deficiency is a genetic disorder of the cellular carnitine-transporter system that typically appears by the age of five with symptoms of cardiomyopathy, skeletal-muscle weakness, and hypoglycemia.<ref name=lpi/><ref name=ods/> Secondary carnitine deficiencies may happen as the result of certain disorders, such as chronic ], or under conditions that reduce carnitine absorption or increase its excretion, such as the use of ]s, ], and poor absorption following ].<ref name=lpi/><ref name=ods/> |
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==Supplementation== |
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===Pharmacokinetics=== |
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The plasma half-life of L-carnitine taken as a supplementation is approximately 17.4 hours.<ref>{{cite journal|date=13 September 2012|doi=10.2165/00003088-200342110-00002|title=Pharmacokinetics of L-Carnitine|publisher=Springer |journal=Clinical Pharmacokinetics |volume=42 |issue=11 |pages=941–967 | vauthors = Evans AM, Fornasini G |pmid=12908852 }}</ref><ref name="pmid32958033"/> |
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===Evidence=== |
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Despite widespread interest among athletes to use carnitine for improvement of exercise performance, inhibit ], or enhance recovery from ], the quality of research for these possible benefits has been low, prohibiting any conclusion of effect.<ref name=lpi/><ref name=ods/> Despite some studies suggest that carnitine may improve high-intensity physical performance,<ref name="pmid34959912">{{cite journal |vauthors=Mielgo-Ayuso J, Pietrantonio L, Viribay A, Calleja-González J, González-Bernal J, Fernández-Lázaro D |title=Effect of Acute and Chronic Oral l-Carnitine Supplementation on Exercise Performance Based on the Exercise Intensity: A Systematic Review |journal=Nutrients |volume=13 |issue=12 |date=December 2021 |page=4359 |pmid=34959912 |pmc=8704793 |doi=10.3390/nu13124359 |url= |doi-access=free }}</ref> and facilitate recovery after such performance,<ref name="pmid29701693">{{cite journal |title=Erratum: l-Carnitine Supplementation in Recovery after Exercise; Nutrients 2018, 10, 349 |journal=Nutrients |volume=10 |issue=5 |date=April 2018 |page=541 |pmid=29701693 |pmc=5986421 |doi=10.3390/nu10050541 |url= |doi-access=free |author1=Nutrients Editorial Office }}</ref> the results of these studies are inconclusive, since various studies used various regimens of carnitine supplementation and intensity of exercise.<ref name="pmid31906370">{{cite journal |vauthors=Gnoni A, Longo S, Gnoni GV, Giudetti AM |title=Carnitine in Human Muscle Bioenergetics: Can Carnitine Supplementation Improve Physical Exercise? |journal=Molecules |volume=25 |issue=1 |date=January 2020 |page=182 |pmid=31906370 |pmc=6982879 |doi=10.3390/molecules25010182 |url= |doi-access=free }}</ref><ref name="pmid33097528">{{cite journal |vauthors=Collins J, Maughan RJ, Gleeson M, Bilsborough J, Jeukendrup A, Morton JP, Phillips SM, Armstrong L, Burke LM, Close GL, Duffield R, Larson-Meyer E, Louis J, Medina D, Meyer F, Rollo I, Sundgot-Borgen J, Wall BT, Boullosa B, Dupont G, Lizarraga A, Res P, Bizzini M, Castagna C, Cowie CM, D'Hooghe M, Geyer H, Meyer T, Papadimitriou N, Vouillamoz M, McCall A |title=UEFA expert group statement on nutrition in elite football. Current evidence to inform practical recommendations and guide future research |journal=Br J Sports Med |volume=55 |issue=8 |pages=416 |date=April 2021 |pmid=33097528 |doi=10.1136/bjsports-2019-101961 |s2cid=225058557 |url=|doi-access=free |hdl=10453/151474 |hdl-access=free }}</ref> At supplement amounts of {{convert|2|–|6|g}} per day over a month, there was no consistent evidence that carnitine affected exercise or physical performance on moderate-intensity exercises, whereas on high-intensity exercises results were mixed.<ref name=ods/> Carnitine supplements does not seem to improve oxygen consumption or metabolic functions when exercising, nor do they increase the amount of carnitine in muscle.<ref name=lpi/><ref name=ods/> The underlying mechanisms on how carnitine can improve physical performance, if at all, are not clearly understood.<ref name="pmid15212755">{{cite journal |vauthors=Karlic H, Lohninger A |title=Supplementation of L-carnitine in athletes: does it make sense? |journal=Nutrition |volume=20 |issue=7–8 |pages=709–15 |date=2004 |pmid=15212755 |doi=10.1016/j.nut.2004.04.003 |url=}}</ref> There is no evidence that L-carnitine influences ] or aids in weight loss.<ref name=ods/><ref name="pmid21951331">{{cite journal |vauthors=Jeukendrup AE, Randell R |title=Fat burners: nutrition supplements that increase fat metabolism |journal=Obes Rev |volume=12 |issue=10 |pages=841–51 |date=October 2011 |pmid=21951331 |doi=10.1111/j.1467-789X.2011.00908.x |s2cid=29708762 |url=|doi-access=free }}</ref><ref name="pmid21561431">{{cite journal |vauthors=Pekala J, Patkowska-Sokoła B, Bodkowski R, Jamroz D, Nowakowski P, Lochyński S, Librowski T |title=L-carnitine--metabolic functions and meaning in humans life |journal=Curr Drug Metab |volume=12 |issue=7 |pages=667–78 |date=September 2011 |pmid=21561431 |doi=10.2174/138920011796504536 |url=}}</ref> |
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=== Male fertility === |
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The carnitine content of seminal fluid is directly related to sperm count and motility, suggesting that the compound might be of value in treating male infertility.<ref name=lpi/> |
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=== Diseases === |
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Carnitine has been studied in various cardiometabolic conditions, indicating it is under preliminary research for its potential as an adjunct in ] and ], among numerous other disorders.<ref name=lpi/> Carnitine has no effect on preventing ] associated with cardiovascular diseases,<ref name="pmid25044037">{{cite journal | vauthors = Shang R, Sun Z, Li H | title = Effective dosing of ʟ-carnitine in the secondary prevention of cardiovascular disease: a systematic review and meta-analysis | journal = BMC Cardiovascular Disorders | volume = 14 | pages = 88 | date = July 2014 | pmid = 25044037 | pmc = 4223629 | doi = 10.1186/1471-2261-14-88 | doi-access = free }}</ref> and has no significant effect on ].<ref name=lpi/><ref name="pmid24525835">{{cite journal | vauthors = Huang H, Song L, Zhang H, Zhang H, Zhang J, Zhao W | title = Influence of ʟ-carnitine supplementation on serum lipid profile in hemodialysis patients: a systematic review and meta-analysis | journal = Kidney & Blood Pressure Research | volume = 38 | issue = 1 | pages = 31–41 | date = 1 January 2013 | pmid = 24525835 | doi = 10.1159/000355751 | doi-access = free }}</ref> |
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Although there is some evidence from ] that L-carnitine supplementation improved cardiac function in people with ], there is insufficient research to determine its overall efficacy in lowering the risk or treating ]s.<ref name=lpi/><ref name="pmid25044037"/> |
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There is only preliminary ] to indicate the use of L-carnitine supplementation for improving symptoms of ], such as improving ] or lowering ] levels of blood ].<ref name=lpi/><ref name="pmid29549241">{{cite journal | vauthors = Bene J, Hadzsiev K, Melegh B | title = Role of carnitine and its derivatives in the development and management of type 2 diabetes | journal = Nutrition & Diabetes | volume = 8 | issue = 1 | pages = 8 | date = March 2018 | pmid = 29549241 | pmc = 5856836 | doi = 10.1038/s41387-018-0017-1 }}</ref> |
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The kidneys contribute to overall ] in the body, including carnitine levels. In the case of ], urinary elimination of carnitine increasing, endogenous synthesis decreasing, and poor nutrition as a result of disease-induced anorexia can result in carnitine deficiency.<ref name=lpi/> Carnitine has no effect on most parameters in end-stage kidney disease, although it may lower ], a ] for systemic ].<ref name="pmid24368434">{{cite journal | vauthors = Chen Y, Abbate M, Tang L, Cai G, Gong Z, Wei R, Zhou J, Chen X | title = ʟ-Carnitine supplementation for adults with end-stage kidney disease requiring maintenance hemodialysis: a systematic review and meta-analysis | journal = The American Journal of Clinical Nutrition | volume = 99 | issue = 2 | pages = 408–22 | date = February 2014 | pmid = 24368434 | doi = 10.3945/ajcn.113.062802 | doi-access = free }}</ref> Carnitine blood levels and muscle stores can become low, which may contribute to ], muscle weakness, fatigue, altered levels of blood fats, and heart disorders.<ref name=lpi/> Some studies have shown that supplementation of high doses of {{sm|l}}-carnitine (often injected) may aid in ] management.<ref name=lpi/> |
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== Sources == |
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The form present in the body is {{sm|l}}-carnitine, which is also the form present in food. Food sources rich in {{sm|l}}-carnitine are animal products, particularly beef and pork.<ref name=lpi/> Red meats tend to have higher levels of {{sm|l}}-carnitine.<ref name=lpi/><ref name="pmid24525835" /> Adults eating diverse diets that contain animal products attain about 23-135 mg of carnitine per day.<ref name=lpi/><ref name="pmid15591001">{{cite journal|last = Rebouche|first = C. J.|title = Kinetics, pharmacokinetics, and regulation of ʟ-carnitine and acetyl-ʟ-carnitine metabolism|journal = ]|volume = 1033|issue = 1|pages = 30–41|year = 2004|pmid = 15591001|doi = 10.1196/annals.1320.003|bibcode = 2004NYASA1033...30R |s2cid = 24803029}}</ref> Vegans get noticeably less (about 10–12 mg) since their diets lack these carnitine-rich animal-derived foods. Approximately 54% to 86% of dietary carnitine is absorbed in the small intestine, then enters the blood.<ref name=lpi/> Even carnitine-poor diets have little effect on total carnitine content, as the kidneys conserve carnitine.<ref name="pmid24525835" /> |
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{| class="wikitable" |
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{| class="wikitable" |
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|+Selected food sources of carnitine<ref name=lpi/> |
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!Food |
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!Milligrams (mg) |
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|Beef steak, cooked, {{convert|4|oz|g}} |
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! Product !! Quantity !! Carnitine |
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|56–162 |
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|Ground beef, cooked, {{convert|4|oz|g}} |
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| Beef steak || 100 g || 95 mg |
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|87–99 |
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| Ground beef || 100 g || 94 mg |
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|Milk, whole, 1 cup (237 g) |
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|8 |
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|Codfish, cooked, {{convert|4|oz|g}} |
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| Pork || 100 g || 27.7 mg |
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|4–7 |
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|Chicken breast, cooked, {{convert|4|oz|g}} |
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| Bacon || 100 g || 23.3 mg |
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|3–5 |
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| ] || 100 g || 19.5 mg |
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|Ice cream, {{frac|1|2}} cup (125 mL) |
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|3 |
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|Cheese, cheddar, {{convert|2|oz|g}} |
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| ] || 100 g || {{nowrap|5.6 mg}} |
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|2 |
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|Whole-wheat bread, 2 slices |
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| Chicken breast || 100 g || 3.9 mg |
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|0.2 |
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|Asparagus, cooked, {{frac|1|2}} cup (62 g) |
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| American cheese || 100 g || 3.7 mg |
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|- |
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|0.1 |
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| Ice cream || 100 ml || 3.7 mg |
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| Whole milk || 100 ml || 3.3 mg |
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| Avocado || one medium || 2 mg<ref></ref> |
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| Cottage cheese || 100 g|| 1.1 mg |
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| Whole-wheat bread|| 100 g || 0.36 mg |
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| Asparagus || 100 g || 0.195 mg |
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| White bread || 100 g || 0.147 mg |
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| Macaroni || 100 g || 0.126 mg |
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| Peanut butter || 100 g || 0.083 mg |
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| Rice (cooked) || 100 g || 0.0449 mg |
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| Eggs || 100 g || 0.0121 mg |
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| Orange juice || 100 ml|| 0.0019 mg |
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|} |
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In general, ] humans each day consume between 2 and 12 ]/kg of body weight, accounting for 75% of carnitine in the body. Humans endogenously produce 1.2 μmol/kg of body weight of carnitine on a daily basis, accounting for 25% of the carnitine in the body.<ref name=lpi/><ref name=ods/> Strict vegetarians obtain little carnitine from dietary sources (0.1 μmol/kg of body weight daily), as it is mainly found in animal-derived foods.<ref name=lpi/><ref name="pmid2756917">{{cite journal | vauthors = Lombard KA, Olson AL, Nelson SE, Rebouche CJ | title = Carnitine status of lactoovovegetarians and strict vegetarian adults and children | journal = The American Journal of Clinical Nutrition | volume = 50 | issue = 2 | pages = 301–6 | date = August 1989 | pmid = 2756917 | doi = 10.1093/ajcn/50.2.301 | doi-access = free }}</ref> |
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L-Carnitine, ], and propionyl-{{sm|l}}-carnitine are available in ] pills or powders, with a daily amount of 0.5 to 1 g considered to be safe.<ref name=lpi/><ref name=ods/> It is also a drug approved by the ] to treat primary and certain secondary carnitine-deficiency syndromes secondary to ].<ref name=lpi/><ref name=ods/> |
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In general, 20 to 200 mg are ingested per day by those on an ] diet, whereas those on a strict ] or ] diet may ingest as little as 1 mg/day.<ref></ref> No advantage appears to exist in giving an oral dose greater than 2 g at one time, since ] studies indicate ] at this dose.<ref>{{cite web|url=http://www.encyclopedia.com/doc/1G1-131086133.html |title=L-carnitine.(Monograph) - Alternative Medicine Review | |publisher=HighBeam Research |date=2005-03-01 |accessdate=2011-03-30}}</ref> |
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== Drug interactions and adverse effects == |
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===Other sources=== |
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Carnitine interacts with ]-conjugated antibiotics such as ]. Chronic administration of these antibiotics increases the excretion of pivaloyl-carnitine, which can lead to carnitine depletion.<ref name=lpi/> Treatment with the ]s ], ], ], or ] significantly reduces blood levels of carnitine.<ref name="Drugs.com-2020-Uses-Benefits-Dosage"/> |
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Other sources may be found in over-the-counter ], ]s and various other products. Products containing <small>L</small>-carnitine cannot be marketed as "natural health products" in ]. <small>L</small>-Carnitine products and supplements are not allowed to be imported into Canada (]).<ref>{{cite web |url=http://www.hc-sc.gc.ca/dhp-mps/prodnatur/bulletins/_communiques/communique_sep05-eng.php |title=NHPD Monthly Communique, Vol. 1, Issue 1, September 2005 |accessdate=2007-06-01 |work=}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> |
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When taken in the amount of roughly {{convert|3|g|oz}} per day, carnitine may cause ], vomiting, abdominal cramps, ], and ] smelling like fish.<ref name=lpi/><ref name="Drugs.com-2020-Uses-Benefits-Dosage"/> Other possible adverse effects include ], muscle weakness, or ]s in people with ].<ref name="Drugs.com-2020-Uses-Benefits-Dosage"/> |
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== History == |
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Levocarnitine was approved by the U.S. ] as a ] under the brand name Carnitor on December 27, 1985.<ref name="Drugs.com-2020-Uses-Benefits-Dosage"/><ref name=pubchem/> |
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== See also == |
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==References== |
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== References == |
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{{reflist}} |
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== External links == |
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