Activity of drug-metabolyzing enzymes in the liver of SWR and C3HA mice sensitive to hepatocarcinogenic action of ortho-aminoazotoluene versus resistant AKR and CC57BR strains

Activity and inducibility of specific markers of cytochrome P4501Al (CYP1A1 ) and IA2 (CyP1A2) 7-ethoxyresorufin-O-deethylase (EROD) and 7-methoxyresor ufin-O-demethylase (MROD) and essential conjugating enzymes (acethyl-, sulf o-, UDP-glucuronosyl- and glutathion-S-transferases) were studied in the li ver of male mice differing in the sensitivity to hepatocarcinogenic action of ortho-aminoazotoluene (OAT). In carcinogenic doses, OAT is shown to be a methylcholanthrene-type inducer of CYPIAI and CYP1A2. No relation is found between the sensitivity of mice to hepatocarcinogenic action of OAT and in ducibility of cytochrome P450 or activity of any conjugating enzymes studie d. it is found, however, that mice sensitive to the carcinogen are characte rized by 1.3-1.8 times elevated EROD:MROD activities relation and 1.7-2.7 d ecreased overall conjugating potencies as compared to resistant mice. The c onclusion is that to the extent that the sensitivity or resistance of mice to induction of liver tumors is depended upon metabolism of OAT, it is dete rmined presumably by balanced activities of the enzymes participating in pr oduction and detoxification of its reactive metabolite(s).