Disease relevance of CYP2B6

• In this study, we describe a novel differentiated human hepatoma cell line (WGA), derived from HepG2, which expresses CYP2B6 and CAR [1].
• Analysis of a panel of fifteen human P450 cDNAs in the baculovirus expression system ('Supersomes') demonstrated that CYP3A4 exhibited the highest N-dechloroethylation activity toward both CPA and IFA, whereas CYP2B6 displayed high N-dechloroethylation activity toward IFA, but not CPA [2].
• CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes [3].
• CYP2B6 and CYP2C19 as the major enzymes responsible for the metabolism of selegiline, a drug used in the treatment of Parkinson's disease, as revealed from experiments with recombinant enzymes [4].
• Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts [5].

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

• P-450 metabolites of arachidonic acid in the control of cardiovascular function [11].
• A varied prevalence of hypergonadotropic hypogonadism in patients with AD and value of steroid-producing cells autoantibodies reactive with steroid 17alpha-hydroxylase or P450 side-chain cleavage enzyme as markers of this disease has been discussed [12].
• As a result of this cascade of events, there is an increase in expression of pituitary POMC/ACTH and key enzymes, e.g. 3 beta-HSD and P-450 17 alpha-hydroxylase, important for de novo cortisol formation by, and consequently maturation of, the fetal adrenal gland [13].
• Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis [14].
• A monoclonal antibody-directed radioimmunoassay was developed that detects epitope-specific cytochromes P-450 in human placentas and peripheral lymphocytes [15].

Chemical compound and disease context of CYP2B6

• Biotransformation of coumarin by rodent and human cytochromes P-450: metabolic basis of tissue-selective toxicity in olfactory mucosa of rats and mice [16].
• The P450 forms responsible for transforming styrene to styrene glycol were determined by analyzing cDNA-expressed individual P450 forms produced in cultured hepatoma G2 cells by recombinant vaccinia viruses [17].
• CONCLUSIONS: A CYP2B6 allelic variant that is more common in African-Americans than in Europeans-Americans was associated with significantly greater efavirenz plasma exposure during HIV therapy [18].
• P-450-mediated activation of 4-ipomeanol to DNA binding metabolites was evaluated using a vaccinia virus complementary DNA expression system and an in situ DNA-binding assay [19].
• Methyl-n-amylnitrosamine (MNAN) induces esophageal cancer in rats, probably involving activation by cytochromes P450 [20].

Biological context of CYP2B6

• Orphenadrine (a CYP2B6 inhibitor) and anti-CYP2B IgG inhibited microsomal cyclophosphamide hydroxylation to a greater extent than ifosphamide hydroxylation, consistent with the 8-fold higher activity of complementary DNA-expressed CYP2B6 with cyclophosphamide [21].
• WGA cells represent a powerful system to study the regulation of CYP2B6 gene expression by PB [1].
• These results show that a novel xenobiotic-responsive enhancer module in the distal region of the CYP2B6 promoter (CYP2B6-XREM) together with the PBREM mediates optimal drug-induced expression of CYP2B6 [22].
• Compared with vehicle controls, PHY administration significantly increased CYP2B6 reporter gene expression, when this reporter construct was delivered together with hCAR expression vector into CAR(-/-) mice [23].
• However, for human CYP2B6 the relatively weak response of the PBREM to PXR and CAR activation in transfection assays fails to describe the potent induction observed in primary human hepatocyte cultures [22].

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

• Intratumoral cytochrome P450 expression conferred substantial sensitivity to CPA cytotoxicity, with the most dramatic effects seen with CYP2B6 [28].
• Furthermore, growth of cultured CYP2A6- and CYP2B6-expressing B-lymphoblastoid cells, but not of CYP-negative control cells, was inhibited by cyclophosphamide and ifosphamide as a consequence of prodrug activation to cytotoxic metabolites [21].
• The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene [29].
• Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin [23].
• The endogenous CYP2B6 gene becomes phenobarbital (PB) inducible in androstenol-treated HepG2 cells either transiently or stably transfected with a nuclear receptor CAR expression vector [29].

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

• Identification of CYP2B6 sequence variants by use of multiplex PCR with allele-specific genotyping [49].
• Analysis of differential substrate selectivities of CYP2B6 and CYP2E1 by site-directed mutagenesis and molecular modeling [50].
• A PXR reporter gene assay in a stable cell culture system: CYP3A4 and CYP2B6 induction by pesticides [51].
• A reconstituted system containing purified CYP2B6, NADPH-reductase, and NADPH-generating system was found to catalyze tamoxifen metabolism to 4-OH-tamoxifen, 4'-OH-tamoxifen, and N-desmethyl-tamoxifen as analyzed by high-performance liquid chromatography analysis [52].
• The activity of CYP2B6 was not recovered after removal of free tamoxifen using spin column gel filtration [52].

References