Induction of cytochrome P-450 in the rat liver after exposure to xylenes, dose-response relationship and dependence on endocrine factors

Male rats were exposed to different concentrations of xylenes for 3 days. Small but statistically significant increases in cytochrome P-450 content, NADPH-cytochrome c reductase activity and O-deethylation of 7-ethoxyresorufin in liver microsomes were detected already at an exposure level of 75 ppm. Morphological studies of livers from rats exposed to relatively high concentrations of xylenes for 5 days showed marked proliferation of smooth ER with little changes of the rough ER. No pathological alterations were observed. Castration of male rats influenced the response to xylene exposure only to a minor extent. Hypophysectomy alone was shown to cause significant increases in cytochrome P-450 and cytochrome b₅ content and epoxide hydrolase activity. Induction of cytochrome P-450 dependent enzymatic activities after exposure to xylenes was reduced but qualitatively similar to that obtained with normal male rats whereas the induction of epoxide hydrolase activity was prevented. The difference in response to exposure to xylenes between male and female rats was mainly quantitative in nature. Polyacrylamide gel electrophoresis of liver microsomes from animals exposed to xylenes in the presence of SDS showed increases in protein bands comigrating with cytochrome P-450 PB-B₂ and epoxide hydrolase purified from phenobarbital treated rats. It is concluded that in the rat exposure to xylenes mimics the effects of phenobarbital treatment as judged by both biochemical and morphological criteria and that the pituitary seems to have a regulatory function with regard to the induction of several drug-metabolizing enzymes.