Estrogen receptor α increases basad and cigarette smoke extract-induced expression of CYP1A1 and CYP1B1, but not GSTP1, in normal human bronchial epithelial cells

Gender-specific estrogen receptor alpha (ER alpha) expression may plausibly influence lung carcinogenesis in females. Initial genome-wide microarray studies confirmed that carcinogen metabolism genes (CYP1A1, CYP1B1) were those most responsive to cigarette smoke extract (CSE) in normal bronchial epithelial (NHBE) cells. These two genes encoding phase I bioactivating enzymes and the GSTP1 gene encoding a phase II deactivating enzyme were then tested for induction by ER alpha. NHBE cells (native ER alpha(-)) were transfected with wild-type ER alpha-adenoviral constructs, and then exposed to CSE, 17 beta-estradiol (EA and/or the ER alpha inhibitor, ICI 182,780. The expression levels of CYP1A 1, CYP1B1, and GSTP1 were then determined by RNA-specific quantitative RT-PCR and immunoassay. ER alpha increased the basal expression of CYP1B1 4.04-fold (P < 0.01) at the mRNA level and 6.5-fold at the protein level. ER alpha also increased the CSE-induced mRNA expression of CYP1B1 2.26-fold (P < 0.01), but not the protein expression. ER alpha did not alter the CYP1A1 mRNA levels, but did increase protein expression 2.0-fold (P < 0.01) on CSE exposure, and 6.2-fold (P < 0.01) upon E-2 exposure. These effects could be inhibited by ICI 182,780. ER alpha did not alter the expression of GSTPI. Chromatin immunoprecipitation assay (ChlP) assay confirmed ER alpha binding to CYP1B1 promoter near the transcription start site. These results suggest that ER alpha regulates the CYP1B1 expression at a transcriptional level, and CYP1A1 expression at a translational level. These data raise the possibility that inter-gender differences in expression of ER alpha that are known to exist in human lung may contribute to inter-individual expression differences in CYP1A1 and CYP1B1, and to differences in carcinogen metabolism and mutation. (c) 2005 Wiley-Liss, Inc.