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CYP2B6  -  cytochrome P450, family 2, subfamily B,...

Homo sapiens

Synonyms: 1,4-cineole 2-exo-monooxygenase, CPB6, CYP2B, CYP2B7, CYP2B7P, ...
 
 
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Disease relevance of CYP2B6

 

Psychiatry related information on CYP2B6

  • These hepatic P450 CYPs come "on line" at different times during fetal and infant development, and each one is discussed in that temporal sequence [6].
  • Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates [7].
  • The relatively low levels of the P-450 isoform present in conceptal brain may be sufficient to generate reactive intermediates that elicit neuroembryotoxicity following maternal alcohol consumption [8].
  • Cytochrome P450 (P450) 3A4, the major catalyst involved in human drug oxidation, displays substrate- and reaction-dependent homotropic and heterotropic cooperative behavior [9].
  • This is the first investigation and demonstration of differences in genetically determined P450 metabolism influencing risk for substance dependence and we suggest that these differences may influence the risk for dependence of other substrate drugs, and may occur with other genetically variable P450s [10].
 

High impact information on CYP2B6

 

Chemical compound and disease context of CYP2B6

 

Biological context of CYP2B6

 

Anatomical context of CYP2B6

  • In primary human hepatocytes, expression of CYP2B6 reporter genes containing phenobarbital-responsive enhancer module (PBREM) or PBREM/xenobiotic-responsive enhancer module (XREM) response elements were activated up to 14- and 28-fold, respectively, by 50 microm PHY [23].
  • Orphenadrine (ORP), a reported specific CYP2B6 inhibitor, was a less potent inhibitor of 7-HFC formation by microsomes from human liver than DDC or ANF [24].
  • However, CYP2B6 is the principal determinant of interindividual variability in the hydroxylation of this drug by human liver microsomes [25].
  • The correlation between the P450 content in this material and P450 in breast epithelium remains to be resolved [26].
  • The expression of cytochrome (CYP) P450 enzymes in human oesophageal mucosa was investigated in a total of 25 histologically non-neoplastic surgical tissue specimens by using specific antibodies in immunoblots and by RT-PCR mRNA analysis [27].
 

Associations of CYP2B6 with chemical compounds

 

Physical interactions of CYP2B6

  • CONCLUSIONS: Proton-pump inhibitors interact with and are metabolized by several human cytochromes P450, but only pantoprazole is also metabolized by a sulfotransferase [30].
  • Taken together with the lack of a kinetically detectable interaction between CYP2B4 and CYP2E1, and the previously reported CYP1A2-CYP2B4 interaction, these results suggest that CYP1A2 may facilitate the formation of complexes with other P450 enzymes [31].
  • The kinetics of CO binding to human cytochrome P450 1A1 was used to probe the interaction of polycyclic aromatic hydrocarbons (PAHs) with the membrane-bound P450 expressed in baculovirus-infected SF9 insect cells [32].
  • The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver [33].
  • Inactivated CYP2B6 did not lose its ability to form a CO-reduced complex suggesting a modification of the apoprotein, which is common for sulfur-containing compounds [34].
 

Enzymatic interactions of CYP2B6

  • CYP2D6 catalyzed diphenhydramine N-demethylation as a high-affinity P450 isozyme, the K(m) value of which was 1.12 +/- 0.21 muM [35].
  • The current study demonstrates that human FMO1 and FMO3 catalyze TAM N-oxidation to TNO and that cytochromes P450 (P450s), but not FMOs, reduce TNO to TAM [36].
  • The effects of P450 isozymes on the kinetic parameters of UGT2B7-catalyzed glucuronidation of the morphine 3-hydroxyl group were examined by simultaneous expression of UGT2B7 and either CYP3A4, -1A2, or -2C9 in COS-1 cells [37].
  • Incubation of olopatadine with cDNA-expressed human p450 isozymes confirmed that M1 formation was almost exclusively catalyzed by CYP3A4 [38].
  • This is the first report that catalase in livers enhances drug oxidation activities catalyzed by P450 in human liver microsomes [39].
 

Regulatory relationships of CYP2B6

  • Taken together, these observations demonstrate that the CYP2B6 gene is directly regulated by PXR and further establish this receptor as a key regulator of drug-metabolizing P450s [40].
  • When assayed at 12 mM BUP, cDNA-expressed CYP3A4 catalyzed BUP hydroxylation at a 30-fold lower rate than cDNA-expressed CYP2B6 (0.2 versus 7 pmol/min/pmol of P450) [41].
  • Moreover, the results suggest that the GR-enhanced expression of CYP2B6 is mediated through an indirect mechanism that does not require increased expression of nuclear receptor [42].
  • Tam metabolism by CYP2D6 coexpressed with P450 reductase in a baculovirus infected insect cell line ("supersomes") exhibited marked tam 4-hydroxylation [43].
  • The sensitivity to geldanamycin and molybdate and the immunodepletion experiments suggest that hsp90 is one of these factors that interact with CYP2E1 and/or with the proteasome to promote the degradation of this microsomal P450 [44].
  • This binding alone is not sufficient to activate the CYP2B6 promoter; the promoter requires EGR1 to enable CAR to activate the CYP2B6 promoter [45].
 

Other interactions of CYP2B6

  • Similar studies indicated that CYP3A4/5 was the major P450 isoform responsible for DCCY formation at high (0.7 and 5 mM) concentrations of CY [46].
  • These results indicated that a PXR-independent pathway, which is retained in primary hepatocytes, is responsible for PHY induction of CYP2B6 [23].
  • When we used the microsomes from treated rats, the metabolite formations did not increase by inducers for CYP1A, CYP2B, CYP2E, CYP3A, or CYP4A, suggesting that these could not be involved in the main metabolic pathway in rats [47].
  • CYP2B6, CYP2D6, and 2C were more easily detected in the carcinoma samples, thus differing from the reduction samples and the epithelial sample [26].
  • Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment [48].
 

Analytical, diagnostic and therapeutic context of CYP2B6

References

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  20. Depentylation of [3H-pentyl]methyl-n-amylnitrosamine by rat esophageal and liver microsomes and by rat and human cytochrome P450 isoforms. Chen, S.C., Wang, X., Xu, G., Zhou, L., Vennerstrom, J.L., Gonzalez, F., Gelboin, H.V., Mirvish, S.S. Cancer Res. (1999) [Pubmed]
  21. Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Chang, T.K., Weber, G.F., Crespi, C.L., Waxman, D.J. Cancer Res. (1993) [Pubmed]
  22. A novel distal enhancer module regulated by pregnane X receptor/constitutive androstane receptor is essential for the maximal induction of CYP2B6 gene expression. Wang, H., Faucette, S., Sueyoshi, T., Moore, R., Ferguson, S., Negishi, M., LeCluyse, E.L. J. Biol. Chem. (2003) [Pubmed]
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  24. Examination of purported probes of human CYP2B6. Ekins, S., VandenBranden, M., Ring, B.J., Wrighton, S.A. Pharmacogenetics (1997) [Pubmed]
  25. Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Court, M.H., Duan, S.X., Hesse, L.M., Venkatakrishnan, K., Greenblatt, D.J. Anesthesiology (2001) [Pubmed]
  26. Characterization of cytochrome P450 enzymes in human breast tissue from reduction mammaplasties. Hellmold, H., Rylander, T., Magnusson, M., Reihnér, E., Warner, M., Gustafsson, J.A. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  27. Characterization of cytochrome P450 expression in human oesophageal mucosa. Lechevrel, M., Casson, A.G., Wolf, C.R., Hardie, L.J., Flinterman, M.B., Montesano, R., Wild, C.P. Carcinogenesis (1999) [Pubmed]
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  34. Inhibition of human CYP2B6 by N,N',N''-triethylenethiophosphoramide is irreversible and mechanism-based. Richter, T., Schwab, M., Eichelbaum, M., Zanger, U.M. Biochem. Pharmacol. (2005) [Pubmed]
  35. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Akutsu, T., Kobayashi, K., Sakurada, K., Ikegaya, H., Furihata, T., Chiba, K. Drug Metab. Dispos. (2007) [Pubmed]
  36. Oxidation of tamoxifen by human flavin-containing monooxygenase (FMO) 1 and FMO3 to tamoxifen-N-oxide and its novel reduction back to tamoxifen by human cytochromes P450 and hemoglobin. Parte, P., Kupfer, D. Drug Metab. Dispos. (2005) [Pubmed]
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  39. Identification of catalase in human livers as a factor that enhances phenytoin dihydroxy metabolite formation by human liver microsomes. Komatsu, T., Yamazaki, H., Nakajima, M., Yokoi, T. Biochem. Pharmacol. (2002) [Pubmed]
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  42. Glucocorticoid receptor enhancement of pregnane X receptor-mediated CYP2B6 regulation in primary human hepatocytes. Wang, H., Faucette, S.R., Gilbert, D., Jolley, S.L., Sueyoshi, T., Negishi, M., LeCluyse, E.L. Drug Metab. Dispos. (2003) [Pubmed]
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