Elevation of hepatic microsomal epoxide hydrolase activity by 2-acetylaminofluorene: role of metabolism.
Brief exposure of rats to hepatocarcinogenic agents causes a rapid elevation in hepatic microsomal epoxide hydrolase (EH) activity. Previous studies have demonstrated that animals which are resistant to the hepatocarcinogenic effects of 2-acetylaminofluorene (AAF) are also resistant to EH induction by this compound. The studies described here were designed to examine the role of several individual metabolic pathways on the induction of EH by AAF. EH was increased 4-fold in male Fischer 344 (F-344) or Sprague-Dawley (SD) rats treated with AAF; in female rats, deficient in N-hydroxylase and sulfotransferase activities, the activity was increased only 2-fold. Pretreatment of male F-344 rats with inducers of cytochrome P-448 activity caused a reduction in the EH response to AAF, probably due to a greater increase in ring-hydroxylation than N-hydroxylation of the AAF. Although AAF elicited only a small EH elevation in female F-344 rats, N-hydroxy-2-acetylaminofluorene (N-OH-AAF) caused a large increase in these animals. The N-OH-AAF-induced increase was partially blocked by pretreatment with pentachlorophenol, an inhibitor of sulfotransferase activity, in both male and female F-344s. In female SD rats, possessing minimal sulfotransferase activity, N-OH-AAF treatment caused only a slight elevation of EH activity. Pretreatment of male F-344 rats with inhibitors of deacetylase activity had no effect on N-OH-AAF-dependent EH induction. These observations are consistent with the suggestion that formation of the sulfate conjugate of N-OH-AAF is necessary for elevation of EH by this compound.
D015073:2-Acetylaminofluorene / Q000494:pharmacology*; D000818:Animals; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D007700:Kinetics; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains
D000072317:Polychlorinated Dibenzodioxins; D008748:Methylcholanthrene; D015073:2-Acetylaminofluorene; D004851:Epoxide Hydrolases