The Effects of Experimental Diabetes on the Cytochrome P450 System and Other Metabolic Pathways
John H. McNeill in Experimental Models of Diabetes, 2018
CYP2B — One of the first subfamilies to be purified from the liver of animals, CYP2B has been extensively studied and shown to display broad substrate specificity.13 Although it metabolizes a large number of known chemical carcinogens, it tends to convert these to inactive metabolites and it is generally unable to convert them to their reactive intermediates.8 An activating role has, however, been ascribed to it in certain instances as in the case of certain long-chain aliphatic nitrosamines and drugs like cocaine and cyclophosphamide, where it acts as the major catalyst for the bioactivation of this anticancer drug to the pharmacologically active form in humans. Like CYP2A, in humans it is a minor form representing less than 2% of the total liver cytochrome P450, the isoforms being CYP2B6 and CYP2B7.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
The human cytochrome P450 CYP2B6 gene is involved in the metabolic activation of a number of clinically important chemotherapeutic drugs for breast cancer, including CP (10,11) as well as the antioestrogen TAM (12). Several single nucleotide polymorphisms (SNPs) in CYP2B6 have been described, some having functional significance (13) and affecting the pharmacokinetic parameters of CP. In cell culture, enzymatic activities in microsomes from COS-1 cells expressing a K262R amino acid substitution (CYP2B6*4, CYP2B6*6, and CYP2B6*7) showed increased values for Vmax and Vmax/Km compared with that of the wild type (CYP2B6*1) (14), while a second study reported that the amino acid substitution Q172H resulting from the CYP2B6*6 allele enhanced 7-ethoxycoumarin O-deethylase activity (15). A study by Lang et al. (2001) identified a total of nine SNPs by sequencing DNA from 35 subjects and reported extensive variability in the expression and activity of CYP2B6, where CYP2B6 expression was significantly reduced in carriers of the R487T, Q172H, and K262R polymorphisms (16). Ethnic variation in allelic variants and CYP2B6 expression has been also been observed (17,18).
Efavirenz
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Higher plasma concentrations of efavirenz are associated with an SNP in the CYP2B6 gene encoding amino acid position 516, resulting in a G (glycine) to T (threonine) substitution. The frequency of the 516G > T allele varies with racial background: homozygosity (TT genotype) occurs in 20% of African Americans but in only 3% of European Americans (Haas et al., 2004). This allele is also more common in ethnic Chinese (Xu et al., 2007), Ghanaians (Klein et al., 2005), and Zimbabweans (Nyakutira et al., 2007). Other polymorphisms affecting CYP2B6 activity have also been identified (Klein et al., 2005; Wang et al., 2006; Rotger et al., 2007b).
Quantitative in vitro phenotyping and prediction of drug interaction potential of CYP2B6 substrates as victims
Published in Xenobiotica, 2018
Raghava Choudary Palacharla, Ramakrishna Nirogi, Venkatesham Uthukam, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Ilayaraja Kalaikadhiban
Cytochrome P450 2B6 enzyme (CYP2B6) is a historically overlooked enzyme but gained attention over a decade due to the discovery of clinically important drugs as its substrates, and genetic polymorphism (Zanger & Klein, 2013). CYP2B6 accounts for 2–10% of total hepatic CYP content, with significant inter-individual variability ranging between 20- and 250-fold in its expression (Wang & Tompkins, 2008). The high inter-individual variability in CYP2B6 expression and activity may lead to variable systemic exposure and therapeutic response of the drugs known to be metabolized by the enzyme. Approximately 8% of the commercial drugs are known to be metabolized by CYP2B6 (Hedrich et al., 2016). CYP2B6 substrates include but are not limited to artemisinin (Svensson & Ashton, 1999), bupropion (Faucette et al., 2000), efavirenz (Ward et al., 2003), ketamine (Yanagihara et al., 2001), propofol (Court et al., 2001; Oda et al 2001), pethidine (Ramírez et al., 2004), methadone (Kharasch & Stubbert, 2013), nevirapine (Erickson et al., 1999), ticlopidine (Talakad et al., 2011), cyclophosphamide (Huang et al., 2000; Roy et al., 1999), clopidogrel (Kazui et al., 2010), sertraline (Obach et al., 2007) and selegiline (Hidestrand et al., 2001; Salonen et al., 2003).
Nuclear receptor co-repressor RIP140 regulates diurnal expression of cytochrome P450 2b10 in mouse liver
Published in Xenobiotica, 2020
Mengjing Zhao, Huan Zhao, Luomin Lin, Yi Wang, Menglin Chen, Baojian Wu
CYP2B6 (Cyp2b10) is one of typical CYP enzymes whose expression can be induced by various xenobiotics including drugs. Expression induction is attributed to activation of nuclear receptors such as constitutive androstane receptor (CAR) and pregnane X receptor (PXR) that function as transcriptional activators of CYPs and other drug-metabolizing enzymes. Phenobarbital is a well-known inducer of CYP2B6 (Cyp2b10) and an agonist of both CAR and PXR (Hardwick et al., 1983; Sueyoshi & Negishi, 2001). Studies have identified a phenobarbital-responsive enhancer module (PBREM) in CYP2B6 (located at −1733/−1683 bp) and Cyp2b10 (located at −2339/−2289 bp) promoters (Honkakoski et al., 1998; Honkakoski & Negishi, 1997; Sueyoshi et al., 1999). Upon stimulation by phenobarbital, CAR and PXR transactivate CYP2B6 and Cyp2b10 through direct binding to the PBREM element (Beigneux et al., 2002; Honkakoski et al., 1998).
Newly identified tree shrew cytochrome P450 2B6 (CYP2B6) and pig CYP2B6b are functional drug-metabolising enzymes
Published in Xenobiotica, 2022
Yasuhiro Uno, Genki Ushirozako, Shotaro Uehara, Norie Murayama, Yuki Fujiki, Hiroaki Kawaguchi, Kyoko Tsukiyama-Kohara, Hiroshi Yamazaki
The cytochromes P450 (P450s or CYPs) constitute a family of haem–thiolate enzymes catalysing the oxidation or reduction reactions of various endogenous and exogenous substrates; in humans, the P450s comprise 57 functional genes and 58 pseudogenes (Nelson et al. 2004). The human CYP2B subfamily contains functional CYP2B6 and pseudogene CYP2B7P, and CYP2B6 constitutes approximately 2–5% of total P450 proteins in human liver (Gervot et al. 1999; Shimada et al. 1999; Lang et al. 2001). Human CYP2B6 metabolises various substrates, including clinically important pharmaceuticals, bupropion, cyclophosphamide, diazepam, efavirenz, and tamoxifen (Lang et al. 2001). Marmoset CYP2B6 and cynomolgus macaque CYP2B6 notably showed unique substrate selectivity; these enzymes do not effectively catalyse efavirenz 8-hydroxylation, unlike human CYP2B6 (Oshio et al. 2019). Human CYP2B6 is also induced by phenobarbital via mechanisms involving nuclear receptors, constitutive androstane receptor, and pregnane X receptor (Wang and Negishi 2003).
Related Knowledge Centers
- Cyp2A6
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