Reduction of androgen receptor expression by benzo[ a]pyrene and 7,8-dihydro-9,10-epoxy-7,8,9,10-tetrahydrobenzo[ a]pyrene in human lung cells

Abstract

5α-Dihydrotestosterone significantly increased cell growth of lung adenocarcinoma cell line H1355. Benzo[ a]pyrene (BaP) was a pulmonary carcinogen found in cigarette smoke. Treatment with 1 μM BaP tremendously reduced constitutive androgen receptor (AR) expression, as determined with Western immunoblotting and the real-time RT–PCR assay, as well as testosterone-induced AR protein levels in H1355 cells. Similarly, 1 μM BaP significantly reduced AR mRNA levels in human bronchial epithelial cells BEAS-2B. Although BaP, 2,3,7,8-tetrachlorodibenzo- p-dixin and polychlorinated biphenyl 126 activated aryl hydrocarbon receptor (AhR), which subsequently induced cytochrome P4501A1 ( CYP1A1) and P4501B1 ( CYP1B1) expression in H1355 cells, unexpectedly, neither TCDD nor PCB126 reduced AR expression. Antagonizing AhR activation and cytochrome P4501 activity with α-naphthoflavone, or inhibiting CYP1B1 activity with 2,4,3′,5′-tetramethoxystilbene, however, prevented BaP-induced AR reduction. Furthermore, 7,8-dihydro-9,10-epoxy-7,8,9,10-tetrahydrobenzo[ a]pyrene, a BaP carcinogenic metabolite catalyzed by CYP1A1 and CYP1B1, significantly reduced AR expression in H1355 cells and human lung fibroblasts WI-38. This was the first study that reports that BaP and BPDE reduced endogenous AR expression. These data suggest that metabolically activated BaP may disrupt androgen function by reducing AR levels in androgen-responsive organs.