INCREASED BASAL EXPRESSION OF HEPATIC CYP1A1 AND CYP1A2 GENES IN INBRED MICE SELECTED FOR SUSCEPTIBILITY TO ACETAMINOPHEN-INDUCED HEPATOTOXICITY

Susceptibility to acetaminophen-induced hepatotoxicity was found to va ry widely in an outbred colony of Swiss Webster mice, Some acetaminoph en-treated male mice showed a significant elevation in serum levels of the hepatic enzyme alanine aminotransferase at a normally non-hepatot oxic oral dose, A selective breeding program over 17 generations produ ced inbred mice which were either susceptible or nonsusceptible to the hepatotoxic effects of acetaminophen. Liver microsomes from the susce ptible group showed a statistically significant increase in the abilit y to metabolize acetaminophen to a reactive intermediate which covalen tly binds N-acetylcysteine. Microsomal cytochrome P450 activities asso ciated with CYP1A2 (acetanilide 4-hydroxylation and methoxyresorufin O -demethylase) were significantly increased in the susceptible group, E thoxyresorufin O-deethylase activity, associated with both CYP1A1 and CYP1A2, was also significantly elevated in this group, Further examina tion of both CYP1A isoforms revealed that hepatic CYP1A1 and CYP1A2 mR NA and protein levels were significantly elevated in animals from the susceptible group, In vivo caffeine 3-demethylation, which is associ- ated with CYP1A2 activity, co-segregated with acetaminophen susceptibi lity and showed a significant positive correlation (r = 0.626, p < 0.0 05) with CYP1A2 mRNA expression in animals from both the susceptible a nd nonsusceptible groups, The co-segregation of elevated basal Cyp1a1 and Cyp1a2 gene expression levels in animals selected for susceptibili ty to acetaminophen-induced hepatotoxicity suggested a common heritabl e basis for regulation of basal expression of both of these CYP1A isof orms, This was supported by the correlated expression of both CYP1A mR NAs within individual mice (r = 0.644, p < 0.02).