Induction and post-transcriptional suppression of hepatic cytochrome p450 1a1 by 3,3′,4,4′-tetrachlorobiphenyl

Abstract

3,3′,4,4′-Tetrachlorobiphenyl (TCB) can induce and inhibit cytochrome P450 1A1 (CYP1A1) in vertebrates. TCB may also suppress CYP1A1 protein levels, but the mechanism is unknown. This study examined transcriptional and translational aspects of hepatic CYP1A1 regulation in the fish scup (Stenotomus chrysops) given single intraperitoneal injections of low (0.1 mg/kg) or high (5 mg/kg) doses of TCB, and sampled over 16 days. The low dose strongly induced hepatic CYP1A1 mRNA (25-fold), protein (12-fold), and activity [ethoxyresorufin O-deethylase (EROD)](15-fold). The high dose also strongly induced CYP1A1 mRNA (29-fold), in a pattern like that at the low dose, but microsomal CYP1A1 protein content was induced only 4-fold and EROD rates were near control levels. Both TCB doses caused similar increases in microsomal cytochrome b 5 content, and in rates of NADPH-cytochrome c (P450) reductase and UDP-glucuronosyltransferase (with p-nitrophenol). The contents of CYP forms other than CYP1A1 (putative CYP2B or CYP3A) were only weakly affected by TCB at either dose. The strong and largely specific post-transcriptional suppression of CYP1A1 content was associated with high concentrations of TCB measured in the liver. Incubation of scup hepatic microsomes with TCB plus NADPH led to a time-dependent inactivation of CYP1A1 that was distinct from catalytic inhibition, and appeared not to involve reactive metabolites of TCB. This in vitro result suggests that TCB may inactivate CYP1A1 in vivo, which could account for the apparent antagonistic effect of TCB on CYP1A1 induction.