Differences in caffeine 3-demethylation activity among inbred mouse strains: a comparison of hepatic Cyp1a2 gene expression between two inbred strains

Fundam Appl Toxicol. 1997 Dec;40(2):228-37. doi: 10.1006/faat.1997.2394.


The 3-demethylation of caffeine can be used as an index of cytochrome P450 CYP1A2 activity in 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. Hepatic Cyp1a2 expression 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.

Publication types

  • Comparative Study

MeSH terms

  • Acetaminophen / administration & dosage
  • Animals
  • Caffeine / administration & dosage*
  • Caffeine / blood
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1A2 / biosynthesis*
  • Cytochrome P-450 CYP1A2 / genetics
  • DNA, Complementary / biosynthesis
  • Female
  • Gene Expression Regulation, Enzymologic / genetics
  • Immunoblotting
  • Male
  • Mice
  • Mice, Inbred Strains
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / enzymology
  • Oligonucleotide Probes
  • Phenotype
  • RNA, Messenger / analysis
  • Sex Factors
  • Theophylline / blood


  • DNA, Complementary
  • Oligonucleotide Probes
  • RNA, Messenger
  • Acetaminophen
  • Caffeine
  • Theophylline
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1A2
  • 1,7-dimethylxanthine