Disease relevance of Cyp2b1

• Cytochrome P450 2B1 mediates oxidant injury in puromycin-induced nephrotic syndrome [1].
• Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganciclovir/herpes simplex virus thymidine kinase gene therapies [2].
• Analyses of the 5' regulatory sequences of genes encoding barbiturate-inducible cytochromes P450BM-1 and P450BM-3 from Bacillus megaterium and of the 5' sequences of genes for barbiturate-inducible P450b and P450e of the rat revealed a string of 17 base pairs in each of the genes that shared a high degree of sequence identity [3].
• Here, we show that brain tumor cells can be sensitized to the cytotoxic effects of CPA, both in culture and in vivo, by introduction of the hepatic enzyme responsible for the activation of CPA, cytochrome P450 2B1 [4].
• Gene therapy for malignant gliomas using replication incompetent retroviral and adenoviral vectors encoding the cytochrome P450 2B1 gene together with cyclophosphamide [5].

High impact information on Cyp2b1

• It also expresses, in infected cells, the cyclophosphamide (CPA)-sensitive rat cytochrome P450 2B1 (CYP2B1) and the ganciclovir (GCV)-sensitive herpes simplex virus thymidine kinase (HSV-TK) transgenes [2].
• DNA cross-linking, assayed by ethidium bromide fluorescence, was significantly inhibited in the presence of GCV, suggesting that interactions between the CPA/CYP2B1 and GCV/HSV-TK gene therapies occurred at the level of DNA repair [2].
• The mixed cultures expressed albumin, A1AT, AFP, transferrin, and CYPIIB1 [6].
• Most significant of these differences was the relatively weak induction of CYPIIB1 but striking induction of CYPIIB2 by tamoxifen [7].
• Tamoxifen was approximately one-tenth as potent an inducer of combined CYPIIB1/2 mRNA compared with phenobarbital when the two drugs were administered at equimolar doses [7].

Biological context of Cyp2b1

• Cytochrome P450 2B1 has been subjected to directed evolution to investigate the role of amino acid residues outside of the active site and to engineer novel, more active P450 catalysts [8].
• Hydroxylation of fatty acids by microsomal and reconstituted cytochrome P450 2B1 [9].
• Furthermore, permethrin stimulated the expression of the luciferase reporter gene under control of the CYP2B1 promoter (comprising the PB-responsive enhancer module) in transiently transfected primary hepatocyte cultures [10].
• It is hypothesized that the evolution of true terrestrialness, and not the evolution of air-breathing lungs alone, is required for the transcriptional activation of CYPIIB gene by PB [11].
• The present study demonstrates that ME inhalation exposure differentially modulates cytochrome P-450 2B1 and antioxidant enzymes and increases susceptibility to lipid peroxidation in rat liver and lung [12].

Anatomical context of Cyp2b1

• With microsomes from PB-pretreated rats, inhibition by mAb-2B1 indicated a 62% contribution by cytochrome P450 2B1 to debutylation of NDBA and 65% to depropylation of NDPA [13].
• Induction of cytochrome P450 2B1 by pyrethroids in primary rat hepatocyte cultures [10].
• 2. Analysis by Western blot showed that PATC induces cytochrome P-450 b, P-450 c and P-450 d, which are the major forms of cytochrome P-450 in liver microsomes of rats when pretreated with phenobarbital and 3-methylcholanthrene [14].
• The differential induction of P450b versus P450e genes in the small intestine and liver indicates that the regulation of these closely linked genes is tissue-specific [15].
• The expression of cytochromes P450b and P450e genes was studied in the small intestinal mucosa of rats using a cDNA which recognizes the mRNAs of both cytochromes as well as oligonucleotide probes which are able to differentiate between the two gene products [15].

Associations of Cyp2b1 with chemical compounds

• Directed evolution of mammalian cytochrome P450 2B1: mutations outside of the active site enhance the metabolism of several substrates, including the anticancer prodrugs cyclophosphamide and ifosfamide [8].
• Ethanol feeding had no apparent effect on steady-state messenger RNA levels of cytochrome P450d, P450b or the multidrug-resistant gene [16].
• Among the tested pyrethroids, permethrin elicited the most pronounced induction of CYP2B1 mRNA, which exceeded maximal induction achieved by PB at concentrations approximately 10-fold higher [10].
• Several metabolites of permethrin formed by hepatocytes (3-(2',2'-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid, 3-phenoxybenzyl alcohol, and 3-phenoxybenzoic acid) were ineffective in inducing CYP2B1 mRNA [10].
• Densitometric quantitation of immunoblots probed with polyclonal antibody against cytochrome P450 2B1 indicated a 17-fold increase in the hepatic level of cytochrome P450 2B1 for rats treated with the highest dose of Telazol [17].

Regulatory relationships of Cyp2b1

• The constitutive androstane receptor (CAR) activates the expression of a reporter gene attached to the phenobarbital-response element (PBRE) of the cytochrome P450 2B1 (CYP2B1) gene in response to the barbiturate phenobarbital and the plant product picrotoxin [18].

Other interactions of Cyp2b1

• Both CYPIA and CYPIIB genes are expressed, as determined by the catalysis of their protein products, during larval, postlarval, and adult stages of R. pipiens [11].
• Western immunoblotting indicated that ethylbenzene treatment induced cytochrome P450 2B1/2B2 to a greater extent in male rats and cytochrome P450 2E1 only in females [19].
• In conclusion, we show that the ERK pathway negatively regulates CYP2B2 enhancer-promoter activity and that, despite p38 activation upon PB exposure, the sensitivity of CYP2B mRNA expression to SB-203580 appears to be unrelated to this kinase [20].
• Regarding the PB (1mM) induction of CYP2B mRNA expression, while chemically inhibiting JNK had no effect, specific inhibitors of the ERK (U0-126) and p38 (SB-203580) pathways up- and down-regulated this expression, respectively [20].
• A model implicating a nuclear heme pool regulating the transcription of delta-aminolevulinate synthase, CYPIIB1/B2, and heme oxygenase genes is proposed [21].

Analytical, diagnostic and therapeutic context of Cyp2b1

• Increases in CYPIIB1, CYPIIB2, CYPIIIA, and microsomal epoxide hydrolase mRNA and protein levels in males and females were observed by Western and Northern blotting [7].
• In parallel with these strain differences in enzyme activities, a decrease in phenobarbital (PB) inducible P450 isozymes, mainly P450b and P450e, was observed by Western blot analysis [22].
• In vivo, regression of 9L s.c. tumor volumes in athymic mice was achieved only by the multimodal treatment allowed by rRp450 viral oncolysis combined with CPA/CYP2B1 and GCV/HSV-TK gene therapies, whereas all other treatment combinations produced only tumor growth retardation [2].
• The location of the P450b mRNA within the intestinal mucosa following treatment with inducers was studied by in situ hybridization; the message was induced predominantly in enterocytes located in intestinal villi [15].
• After treatment with each of the compounds, P450b mRNA was markedly induced in small intestinal mucosa and in liver [15].

References