Substrate Specificity, Regulation, and Polymorphism of Human Cytochrome P450 2B6

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 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.

Carbonated soft drinks alter hepatic cytochrome P450 isoform expression in Wistar rats

“…Furthermore, metformin was recently demonstrated to enhance constitutive active/androstane receptor (CAR) phosphorylation in human hepatocytes in part via an AMPK-dependent signaling pathway and suppression of CYP2B6 (37). Thus, the suppressive effect of SDs on CYP2B1 mRNA expression, which was revealed in the current study, may be mediated through caffeine stimulation of AMPK-dependent enhancement of CAR phosphorylation (38).…”

Cytochrome P450–mediated drug metabolism in the brain

“…9 Members of families 1, 2 and 3 primarily metabolize xenobiotics, such as drugs and environmentally derived compounds, and some endogenous substrates, whereas other vertebrate CYP family members primarily metabolize endogenous compounds. 5,7,[10][11][12] The CYP2 family metabolizes a large proportion of CNS-acting pharmacologics, such as antidepressants and antipsychotics; drugs of abuse, such as amphetamine and ethanol; and some endogenous neurochemicals, such as dopamine and serotonin. Some examples are presented in Tables 1 and 2.…”

In Vitro Inhibitory Effect of Licoricidin on Human Cytochrome P450s

“…CYP2B6 has been estimated to represent approximately 1-10% of the total hepatic CYP content and metabolize approximately 8% of clinically used drugs (n > 60) and endogenous materials. 11,12 CYP2B6 is one of the CYP enzymes that bioactivates several procarcinogens and toxicants.…”