Pharmacogenetics and Regulation of Human CytochromeP450 1B1: Implications in Hormone-Mediated Tumor Metabolism and a Novel Target for Therapeutic Intervention

Abstract

Several of the hormone-mediated cancers (breast, endometrial, ovarian, and prostate) represent major cancers in both incidence and mortality rates. The etiology of these cancers is in large part modulated by the hormones estrogen and testosterone. As advanced disease develops, the common treatment for these cancers is chemotherapy. Thus, genes that can alter tissue response to hormones and alter clinical response to chemotherapy are of major interest. The cytochrome P450 1B1 (CYP1B1) may be involved in disease progression and modulate the treatment in the above hormone-mediated cancers. This review will focus on the pharmacogenetics of CYP1B1 in relation to hormone-mediated cancers and provide an assessment of cancer risk based on CYP1B1 polymorphisms and expression. In addition, it will provide a summary of CYP1B1 gene regulation and expression in normal and neoplastic tissue. (Mol Cancer Res 2006;4(3):135 -50)

Impact of Smoking Cessation on Global Gene Expression in the Bronchial Epithelium of Chronic Smokers

“…Seven of the eight validated genes overexpressed in current smokers-CYP1B1, four AKRs, ALDH3A1, and NQO1 (Table 2)-are involved in drug and/or carcinogen metabolism (9,10,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Polycyclic aromatic hydrocarbons in tobacco smoke are known to bind to and activate the aryl hydrocarbon receptor and thus induce CYP1B1 (10).…”

“…CYP1B1 expression is of special interest because it may contribute both to increased drug metabolism and to carcinogenesis of the aerodigestive tract (1,(18)(19)(20). The metabolic clearance of docetaxel, tamoxifen, gefitinib, erlotinib, and other cancer prevention and therapy drugs is enhanced by YP1B1 (9,(21)(22)(23). Upregulation of CYP1B1 and the six other validated overexpressed metabolizing genes by smoking is likely involved in the adverse interactions between smoking and drugs for lung cancer prevention and therapy; smoking cessation down-regulates these gene expressions and thus may reduce or eliminate the adverse drug interactions.…”

Pharmacogenetic analysis of paclitaxel transport and metabolism genes in breast cancer

“…14 The CYP1B1*3 polymorphism has been associated with increased CYP1B1 mRNA expression, 15 increased catalytic activity [16][17][18] and specifically altered estrogen hydroxylation activity with the potential to interfere with tumor biology. 17,[19][20][21] Overexpression of the adenosine triphosphate-binding cassette transporters ABCB1 and ABCG2 has been associated with resistance to taxane-based agents in vitro, 22 although there is minimal evidence to suggest a role for paclitaxel as a substrate for ABCG2. ABCB1 appears to be the main paclitaxel transporter 23,24 and variants in ABCB1 have been demonstrated to alter P-glycoprotein expression.…”

Preferential Induction of CYP1A1 over CYP1B1 in Human Breast Cancer MCF-7 Cells after Exposure to Berberine

“…The lack of correlation between the CYP1B1 transcripts and protein levels was reported also in the previous studies (Sissung et al, 2006;Sarah et al, 2008;Szaefer et al, 2012). The difference between mRNA expression and the corresponding protein levels may indicate that the translation mechanism is saturated in the conditions of enhanced transcription.…”