DIFFERENCES IN CAFFEINE 3-DEMETHYLATION ACTIVITY AMONG INBRED MOUSE STRAINS - A COMPARISON OF HEPATIC CYP1A2 GENE-EXPRESSION BETWEEN 2 INBRED STRAINS

The 3-demethylation of caffeine can be used as an index of cytochrome P450 CYP1A2 activity in vivo. We compared the plasma levels of caffein e and the 3-demethylated metabolite, 1,7-dimethylxanthine, in six comm on inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J, and SWR/J) and o ne inbred strain (APN) derived in our laboratory from outbred Swiss-We bster mice on the basis of its relative susceptibility to acetaminophe n-induced hepatotoxicity. We found significant variations between a nu mber of the common strains, all of which produced significantly higher caffeine 3-demethylation indices than our APN strain. In three of the six common strains, there was a significant difference between males and females, with the females having consistently lower 1,7-xanthine/c affeine ratios. Hepatic Cyp1a2 expression was compared between APN and C3H/HeJ males, Microsomal methoxyresorufin O-demethylation, acetanili de 4-hydroxylation, and CYP1A2 immunoreactive protein levels were sign ificantly higher in C3H/HeJ relative to APN mice, as were hepatic CYP1 A2 mRNA levels, These results indicate the importance of strain and ge nder to the outcome of pharmacological or toxicological studies involv ing CYP1A2-mediated metabolism, as well as the suitability of the plas ma 1,7-dimethylxanthine/caffeine ratio as a marker of CYP1A2 activity in the mouse. The striking differences observed between the APN and C3 H/HeJ mice suggest that these strains may be suitable for a genetic an alysis of the regulation of the basal expression of CYP1A2, a key enzy me in procarcinogen activation. (C) Society of Toxicology.