Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6

Mo, Sui-Lin, Liu, Ya-He, Duan, Wei, Wei, Ming Qian, Kanwar, Jagat R. and Zhou, Shu-Feng 2009, Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6, Current drug metabolism, vol. 10, no. 7, pp. 730-753.

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Title Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6
Author(s) Mo, Sui-Lin
Liu, Ya-He
Duan, Wei
Wei, Ming Qian
Kanwar, Jagat R.
Zhou, Shu-Feng
Journal name Current drug metabolism
Volume number 10
Issue number 7
Start page 730
End page 753
Total pages 24
Publisher Bentham Science Publishers Ltd.
Place of publication Hilversum, The Netherlands
Publication date 2009-09
ISSN 1389-2002
1875-5453
Keyword(s) CYP2B6
substrate
inducer
nuclear receptor
polymorphism
inhibitor
Summary CYP2B6 is mainly expressed in the liver that has been thought historically to play an insignificant role in human drug metabolism. However, increased interest in this enzyme has been stimulated by the discovery of polymorphic and ethnic differences in CYP2B6 expression, identification of additional substrates for CYP2B6, and evidence for co-regulation with CYP3A4. This paper updates our knowledge about the structure, function, regulation and polymorphism of CYP2B6. CYP2B6 can metabolise approximately 8% of clinically used drugs (n > 60), including cyclophosphamide, ifosfamide, tamoxifen, ketamine, artemisinin, nevirapine, efavirenz, bupropion, sibutramine, and propofol. CYP2B6 is one of the CYP enzymes that bioactivate several procarcinogens and toxicants. This enzyme also metabolizes arachidonic acid, lauric acid, 17beta-estradiol, estrone, ethinylestradiol, and testosterone. Typical substrates of CYP2B6 are non-planar molecules, neutral or weakly basic, highly lipophilic with one or two hydrogen-bond acceptors. The crystal structure of CYP2B6 has not been resolved, while several pharmacophore and homology models of human CYP2B6 have been reported. Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. Pregnane X receptor and glucocorticoid receptor also play a role in the regulation of CYP2B6. Induction of CYP2B6 may partially explain some clinical drug interactions observed. For example, coadministered carbamazepine decreases the systemic exposure of bupropion. There is a wide interindividual variability in the expression and activity of CYP2B6. Such a large variability is probably due to effects of genetic polymorphisms and exposure to drugs that are inducers or inhibitors of CYP2B6. To date, at least 28 allelic variants and some subvariants of CYP2B6 (*1B through *29) have been described and some of them have been shown to have important functional impact on drug clearance and drug response. For example, the efavirenz plasma levels in African-American subjects with the CYP2B6 homozygous 516T/T genotype are approximately 3-fold higher than individuals carrying the homozygous G/G genotype. The CYP2B6 516T/T genotype is associated with 1.7-fold greater plasma levels of nevirapine in HIV-infected patients. Smokers with the 1459C>T (R487C) variant of CYP2B6 may be more vulnerable to abstinence symptoms and relapse following treatment with bupropion as a smoking cessation agent. Further studies in the structure, function, regulation and polymorphism of CYP2B6 are warranted.
Language eng
Field of Research 111603 Systems Physiology
111504 Pharmaceutical Sciences
030405 Molecular Medicine
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2009, Benthan Science Publishers Ltd.
Persistent URL http://hdl.handle.net/10536/DRO/DU:30029303

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