Disease relevance of CYP1B1

• These data suggest that the CYP1B1 polymorphisms in exon 3 are not associated with increased breast cancer risk but that the m1 polymorphism may be functionally important for steroid receptor expression in breast cancer of Caucasian patients [1].
• We hypothesize that polymorphisms of CYP1B1 gene can predict higher incidence of endometrial cancer [2].
• The CYP1B1/1A1 ratio is a critical determinant of the metabolism and toxicity of estradiol in mammary cells [3].
• In contrast, we identified a CYP1B1 germ line heterozygous mutation in 4 of 32 women presenting HNF1alpha-mutated adenomas compared with none in 58 controls [4].
• Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma [4].
• Positive CYP1B1 staining was seen in 81% of glioblastomas, 84% of anaplastic astrocytomas, 61% of oligodendrogliomas, and 67% of anaplastic oligodendrogliomas [5].

Psychiatry related information on CYP1B1

• Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05) [6].
• The results suggest that the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95% CI=1.1-2.2), especially in association with alcohol consumption (P for interaction=0.04), whereas the CYP1B1 Leu(432)Val polymorphism appears to play no role here [7].

High impact information on CYP1B1

• Tumors may be initiated by metabolic conversion of E2 to 4-hydroxyestradiol catalyzed by a specific 4-hydroxylase (CYP1B1) and by further activation of this catechol to reactive semiquinone/quinone intermediates [8].
• Estradiol 4-hydroxylation appears to be a characteristic reaction catalyzed by human CYP1B1 [9].
• We also propose that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway [10].
• By a combination of single-strand conformation polymorphism and direct cycle sequencing, MYOC mutations were detected in 8 (13.3%) of the 60 individuals, CYP1B1 mutations were detected in 3 (5%) of the 60 individuals, and no PITX2 mutations were detected [10].
• CYP1B1 mutations involved cases of juvenile open-angle glaucoma, as well as cases of congenital glaucoma [10].

Chemical compound and disease context of CYP1B1

• Because of the preeminent role of CYP1B1 in mammary estrogen/carcinogen metabolism, we examined the CYP1B1 gene to determine whether genetic differences could account for interindividual differences in breast cancer risk [1].
• PURPOSE: Cytochrome P450 1B1 (CYP1B1), a dioxin inducible member of the CYP supergene family, is overexpressed in various human malignancies including prostate cancer [11].
• The methylation status of the CYP1B1 gene was analyzed in 175 prostate cancer and 96 benign prostatic hyperplasia samples using methylation-specific PCR (MSP) and bisulfite-modified DNA sequencing [11].
• Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens [12].
• The smokers carrying the Val CYP1B1 allele associated with a high hydroxylation activity had a higher risk of breast cancer than never smokers with the Leu/Leu genotype (ORi=2.32, 95%CI: 1.00-5.38) [13].

Biological context of CYP1B1

• The results of our study demonstrated that the distributions of CYP1B1 genotypes at codons 119 and 432 were significantly different between endometrial cancer patients and healthy normal controls [2].
• Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage [14].
• Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics [14].
• Requirement of Aryl Hydrocarbon Receptor Overexpression for CYP1B1 Up-Regulation and Cell Growth in Human Lung Adenocarcinomas [15].
• We hypothesized that promoter/enhancer CpG methylation contributes to the regulation of CYP1B1 expression in human prostate tissue [11].

Anatomical context of CYP1B1

• These results show that xenoestrogens, by altering the ratio of CYP1B1/CYP1A1, could redirect estradiol metabolism in a more toxic pathway in the breast cell line MCF-7 [3].
• The estradiol metabolites by CYP1B1 received particular attention because of their causative role in malignant transformation of endometrium [2].
• In addition, an E229K CYP1B1 mutation was found in a woman with a germ line HNF1alpha mutation in a familial adenomatosis context [4].
• Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells [16].
• In contrast, differences between NOK and SVpgC2a, e.g., for CYP1B1, may reflect alteration caused by immortalization and aid identification of early stage tumor markers in oral epithelium [17].

Associations of CYP1B1 with chemical compounds

• We did an ethoxyresorufin O-deethylase assay to evaluate the functional consequence of the CYP1B1 mutations [4].
• 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) induced expression of CYP1B1 in MCF-7 cells is increased by Trx-1 [18].
• The tyrosine kinase inhibitor genistein and the protein kinase C inhibitor staurosporine blocked TCDD-elicited induction of CYP1A1, but they did not affect CYP1B1 induction [19].
• Protein phosphatase inhibitors okadaic acid and calyculin A enhanced TCDD-induction of CYP1B1 slightly, but had negligible effects on CYP1A1 induction [19].
• Surprisingly, the increased constitutive expression in anti-estrogen-resistant cells of CYP1A1 and CYP1B1 mRNAs, encoding detoxification enzymes, had no effect on the activity of the ICI 182780 compound [20].

Enzymatic interactions of CYP1B1

• We examined the substrate oxidation activities of recombinant human CYP1B1 in yeast microsomes and compared these activities with those catalyzed by reconstituted systems containing recombinant CYP1A1 and CYP1A2 which were isolated from membranes of Escherichia coli in which respective cDNAs have been expressed [21].

Regulatory relationships of CYP1B1

• CONCLUSIONS: In the absence of exogenous AhR ligands (such as cigarette smoke components), AhR overexpression up-regulated the expression of CYP1B1 in the early stage of lung adenocarcinoma [15].
• These results suggest that CYP1A1 and CYP1B1 are differentially regulated in human pulmonary epithelial cells and give the first indication of the induction of CYP3A5 by glucocorticoids in human lung cells [19].
• Overall, our novel findings indicate the upregulation of CYP1B1 by ATRA in HL-60 human promyelocytic leukemic cells shown for the first time to express PXR but not CAR mRNA [22].
• Because CYP1B1 is known to be involved in mammary estrogen metabolism, we investigated whether the estrogen receptor status is influenced by the CYP1B1 genotypes [1].
• An AHH-1 TK+/- cell derivative was developed that stably expresses human cytochrome P4501B1 (CYP1B1) cDNA in an extrachromosomal vector which confers resistance to 1-histidinol and co-expresses NADPH cytochrome P450 oxidoreductase (OR) [23].

Other interactions of CYP1B1

• In multivariate analyses, gender, tobacco smoke exposure, and other factors were associated with the level of expression of CYP1B1, GSTP1, and other transcripts on a gene-specific basis, but substantial interindividual variability in mRNA expression remained unexplained [24].
• These forms were present also in the reduction samples, with CYP2E1 and CYP1B1 being detected in all samples [25].
• We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes [12].
• Alternatively, the Val CYP1B1 or His SULT1A1 allele with modified ability to metabolize estrogens could increase the level of genotoxic catechol estrogen (i.e., 4-hydroxy-estradiol) among smokers [13].
• Generally, induction of CYP1A1, CYP1A2, and CYP1B1 is considered cardiotoxic through generating reactive oxygen species (ROS), DNA adducts, and endogenous arachidonic acid metabolites [26].

Analytical, diagnostic and therapeutic context of CYP1B1

• To test this hypothesis, the genetic distributions of six different CYP1B1 gene polymorphisms were investigated, by sequence-specific PCR and direct DNA sequencing, in 113 Japanese endometrial cancer patients and 202 healthy controls [2].
• EXPERIMENTAL DESIGN: AhR, CYP1B1, and CYP1A1 expression was examined in 107 lung adenocarcinomas and 57 BAC by immunohistochemistry [15].
• We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls) [12].
• We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk [12].
• Further analysis by RT-PCR did not detect the induction of CYP1A1, CYP1A2, or CYP1B1 message in response to 10(-7) M TCDD, 10(-5) M benzanthracene, or 10(-5) M 3-methylcholanthrene [27].

References