Glutathione regulates 3,3',4,4'-tetrachlorobiphenyl induced cytochrome P450 metabolism: evidence for a cross-talk between the two 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 in rainbow trout (Oncorhynchus mykiss). Hepatic glutathione status of tetrachlorobiphenyl injected fish could be successfully manipulated by injecting (i.p.) glutathione or L-buthionine-[S,R]-sulfoximine to arrest glutathione synthesis. Tetrachlorobiphenyl injection resulted in a 17-fold increase in CYP1A catalytic (ethoxyresorufin O-deethylase [EROD]) activity. This effect was further potentiated by 2.7-fold in fish in which hepatic glutathione content was elevated by 3.6-fold. The induction of EROD activity by tetrachlorobiphenyl was 7-fold lower in glutathione deficient (78%) liver. Hepatic glutathione deficiency also downregulated tetrachlorobiphenyl-induced CYP1A gene expression as indicated by lower CYP1A RNA levels. Elevated hepatic glutathione did not influence tetrachlorobiphenyl-induced CYP1A RNA level, but enhanced CYP1A protein expression. These enzyme activity, RNA and protein expression data present compelling evidence suggesting the involvement of tissue glutathione in the regulation of tetrachlorobiphenyl-induced cytochrome P450 dependent metabolism.