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  • 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
    Griffith University Author(s)
    Wei, Ming Q.
    Year published
    2009
    Metadata
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    Abstract
    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 ~8% of clinically used drugs (n>60), including cyclophosphamide, idosfamide, tamoxifen, ketamine, artemisinin, nevirapine, efavirenz, ...
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    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 ~8% of clinically used drugs (n>60), including cyclophosphamide, idosfamide, 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, 17B-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/NR113) which can activate CYP2B6 expression upon ligand binding. Pregane X receptor and glucocortinoid receptor also play a role in the regulation of CYP2B6. Induction of CYP2B6 may partially explain some clinical drug interactions observed. Fro example, coadministered carbamazepine decreases the systemic exposure of bupropion. There is a wide interindividual variability on 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. ti date, at least 28 allelic variants and some subvariants of CYP2B6 (81B 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 ~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.
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    Journal Title
    Current Drug Metabolism
    Volume
    10
    Issue
    7
    Publisher URI
    http://www.benthamdirect.org/pages/content.php?CDM/2009/00000010/00000007/0006F.SGM
    Subject
    Clinical Sciences not elsewhere classified
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/30393
    Collection
    • Journal articles

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