GLUTATHIONE REGULATES 3,3',4,4'-TETRACHLOROBIPHENYL INDUCED CYTOCHROME-P450 METABOLISM - EVIDENCE FOR A CROSS-TALK BETWEEN THE 2 MAJOR DETOXICATION PATHWAYS

The cytochrome P450 and the glutathione systems are two major pathways of xenobiotic metabolism. We tested the effect of hepatic glutathione content on P450 CYP1A1/2 induction by 3,3',4,4'-tetrachlorobiphenyl i n rainbow trout (Oncorhynchus mykiss). Hepatic glutathione status of t etrachlorobiphenyl injected fish could be successfully manipulated by injecting (i.p.) glutathione or L-buthionine-[S,R]-sulfoximine to arre st glutathione synthesis. Tetrachlorobiphenyl injection resulted in a 17-fold increase in CYP1A catalytic (ethoxyresorufin O-deethylase [ERO D]) activity. This effect was further potentiated by 2.7-fold in fish in which hepatic glutathione content was elevated by 3.6-fold. The ind uction of EROD activity by tetrachlorobiphenyl was 7-fold lower in glu tathione deficient (78%) liver. Hepatic glutathione deficiency also do wnregulated tetrachlorobiphenyl-induced CYP1A gene expression as indic ated by lower CYP1A RNA levels. Elevated hepatic glutathione did not i nfluence tetrachlorobiphenyl-induced CYP1A RNA level, but enhanced CYP 1A protein expression. These enzyme activity, RNA and protein expressi on data present compelling evidence suggesting the involvement of tiss ue glutathione in the regulation of tetrachlorobiphenyl-induced cytoch rome P450 dependent metabolism.