Differences in Caffeine 3-Demethylation Activity among Inbred Mouse Strains: A Comparison of HepaticCyp1a2Gene Expression between Two Inbred Strains

Abstract

The 3-demethylation of caffeine can be used as an index of cytochrome P450 CYP1A2 activityin vivo.We compared the plasma levels of caffeine and the 3-demethylated metabolite, 1,7-dimethylxanthine, in six common inbred strains (A/J, P/J, BALB/cJ, C3H/HeJ, AKR/J, and SWR/J) and one inbred strain (APN) derived in our laboratory from outbred Swiss–Webster mice on the basis of its relative susceptibility to acetaminophen-induced hepatotoxicity. We found significant variations between a number 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/caffeine ratios. HepaticCyp1a2expression was compared between APN and C3H/HeJ males. Microsomal methoxyresorufin O-demethylation, acetanilide 4-hydroxylation, and CYP1A2 immunoreactive protein levels were significantly higher in C3H/HeJ relative to APN mice, as were hepatic CYP1A2 mRNA levels. These results indicate the importance of strain and gender to the outcome of pharmacological or toxicological studies involving CYP1A2-mediated metabolism, as well as the suitability of the plasma 1,7-dimethylxanthine/caffeine ratio as a marker of CYP1A2 activity in the mouse. The striking differences observed between the APN and C3H/HeJ mice suggest that these strains may be suitable for a genetic analysis of the regulation of the basal expression of CYP1A2, a key enzyme in procarcinogen activation.