| Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes. | |
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MedLine Citation:
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PMID: 8627511 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Nicotine is primarily metabolized to cotinine, and cotinine is further metabolized to trans-3'-hydroxycotinine in human liver, which is a major metabolite of nicotine in humans. We studied the formation of trans-3'-hydroxycotinine from cotinine in human liver microsomes. trans-3'-Hydroxycotinine formation demonstrated single enzyme Michaelis-Menten kinetics (Km, 234.5 +/- 26.8 MicroM; Vmax, 37.2 +/- 2.4 pmol/min/mg protein). Significant correlation (r = .967, P < .001) between cotinine 3'-hydroxylase activities at low (50 microM) and high (1 microM) cotinine concentrations in 20 human liver microsomes suggested the contribution of a single enzyme to cotinine 3'-hydroxylation. The cotinine 3'-hydroxylase activity correlated significantly with immunoreactive cytochrome P450 (CYP)2A6 contents (r = .756, P < .01) and coumarin 7-hydroxylase activity (r = .887, P < .001). The cotinine 3'-hydroxylase activity was inhibited by coumarin, alpha-naphthoflavone, chlorzoxazone and anti-rat CYP2A1 antibodies. Microsomes of B-lymphoblastoid cells expressing human CYP2A6 exhibited cotinine 3'-hydroxylase activity. The Km value of the expressed CYP2A6 (264.7 microM) was almost identical to that of human liver microsomes. In conclusion, cotinine 3'-hydroxylation appears to be catalyzed solely by CYP2A6 in humans. Cotinine is a candidate for a new substrate for CYP2A6 in humans. |
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Authors:
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M Nakajima; T Yamamoto; K Nunoya; T Yokoi; K Nagashima; K Inoue; Y Funae; N Shimada; T Kamataki; Y Kuroiwa |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 277 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 1996 May |
Date Detail:
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Created Date: 1996-06-27 Completed Date: 1996-06-27 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 1010-5 Citation Subset: IM |
Affiliation:
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Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Aryl Hydrocarbon Hydroxylases* Cotinine / metabolism* Cytochrome P-450 Enzyme System / antagonists & inhibitors, physiology* Humans Hydroxylation Isoenzymes / physiology Microsomes, Liver / metabolism* Mixed Function Oxygenases / antagonists & inhibitors, physiology* |
| Chemical | |
Reg. No./Substance:
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0/Isoenzymes; 486-56-6/Cotinine; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.1/Aryl Hydrocarbon Hydroxylases; EC 1.14.14.1/coumarin 7-hydroxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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