REGULATION OF 3,3',4,4'-TETRACHLOROBIPHENYL INDUCED CYTOCHROME-P450 METABOLISM BY THIOLS IN TISSUES OF RAINBOW-TROUT

We observed that glutathione (GSH) status regulates the Ah receptor in ducible cytochrome P4501A (CYP1A) gene expression and catalytic activi ty in 3,3',4,4'-tetrachlorobiphenyl (TCB) exposed rainbow trout: Tissu e GSH status of TCB (1 mg/kg body weight, in corn oil) injected fish w as manipulated by a) injecting (i.p.) GSH (0.25 g/kg), b) arresting GS H synthesis by L-buthionine-[S,R]-sulfoximine (BSO; 6 mmol/kg) injecti on for 3 and 6 days. Our attempt to manipulate GSH levels by lipoate s upplementation (16 mg/kg) was not productive. Both BSO-and lipoate-sup plemented fish maintained a low tissue redox (GSSG/GSH) ratio. Activit ies of glutathione peroxidase and glutathione reductase were elevated following 3 days of GSH supplementation in GSH rich tissues. Low activ ities of these enzymes were observed in BSO treated GSH deficient tiss ues. TCB injection markedly induced hepatic and renal CYP1A catalytic (ethoxyresorufin O-deethylase [EROD]) activities. This effect was furt her potentiated (3-fold) in GSH-supplemented fish tissues. In contrast , EROD induction by TCB was markedly suppressed in GSH deficient (BSO- treated) and lipoate-supplemented fish. The suppression of CYP1A catal ytic activities in GSH deficient and lipoate-supplemented fish was con sistently associated with a suppression of TCB induced CYP1A mRNA and protein expressions in these groups. In glutathione supplemented fish, TCB induced CYP1A protein expression was markedly higher following ? days of GSH supplementation. Results of our study suggest that tissue thiol status modulates cytochrome P450 CYP1A gene expression and catal ytic activity. (C) 1997 Elsevier Science Inc.