Inductive and inhibitory effects of non-ortho-substituted polychlorinated biphenyls on estrogen metabolism and human cytochromes P450 1A1 and 1B1

The effects of a series of non-ortho-substituted polychlorinated biphenyls (PCBs) on human cytochrome P450 1A1 (CYP1A1), a 17 beta-estradiol (E-2) 2-h ydroxylase, and P450 1B1 (CYF1B1), an E-2 4-hydroxylase, were investigated. in HepG2 and MCF-7 cells. Elevated rates of 2- and 4-methoxyestradiol (2- and 4 MeOE2) formation in PCB-treated cultures were measured as activities of CYP1A1 and CYP1B1, respectively. Of the congeners investigated, 3,4,4',5 -tetrachlorobiphenyl (PCB 81), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), a nd 3,4',5-trichlorobiphenyl (PCB 39) caused marked stimulation of E-2 metab olism in both cell lines. Northern blot analyses confirmed that exposure of MCF-7 cells to PCBs 81, 126, and 39 caused highly elevated levels of the C YP1A1 and CYP1B1 mRNAs. Exposure of MCF-7 cells to 3,3',4,4',5,5'-hexachlor obiphenyl (PCB 169) resulted in elevated levels of the CYP1A1 and CYP1B1 mR NAs, but did nut cause elevated rates of E-2 metabolism; rather, 4-MeOE2 pr oduction was depressed to below control levels in PCB 169-treated cultures. PCB 169 also inhibited the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-indu ced 4-MeOE2 and, to a lesser extent, 2-MeOE2 production in MCF-7 cells, as did PCB 126 and several other congeners. In microsomal assays, inhibition o f cDNA-expressed human CYP1B1 by PCBs 169 and 126 was demonstrated. These s tudies with one subgroup of PCBs, the non ortho-substituted congeners, unde rscore the complexity and diversity of effects of PCBs, as individual conge ners were found both to induce expression and to inhibit activity of human CYP1B1 and CYP1A1. BIOCHEM PHARMACOL 58;1:29-38, 1999. (C) 1999 Elsevier Sc ience Inc.