Abstract
Caffeine metabolite ratios have been widely used to measure cytochrome P-450 1A2 activity in humans. Serum paraxanthine/caffeine ratio is one such index of this activity. We had previously demonstrated genetic variation of this trait among inbred mouse strains. In the present study, we have undertaken a genome-wide scan for quantitative trait loci affecting this trait with an interval mapping approach on an F2 intercross population of acetaminophen nonsusceptible and C3H/HeJ inbred mice. A statistically significant association (log-likelihood ratio = 25.0) between a locus on chromosome 9, which colocalized with the murineCyp1a2 locus, and the plasma paraxanthine/caffeine ratio was identified. This result suggested the presence of an expression polymorphism affecting this gene. A second locus was identified on chromosome 1 (log-likelihood ratio = 9.7) for which no obvious candidate gene has been identified. The influence of this locus on the paraxanthine/caffeine index was more significant among males (log-likelihood ratio = 6.3) than females (log-likelihood ratio = 3.6). A third locus was identified on chromosome 4 with a less statistically robust association (log-likelihood ratio = 3.4) to the paraxanthine/caffeine phenotype. Collectively, these three loci accounted for 63.2% of the variation observed in the F2population for this phenotype. These results demonstrate the potential for genetic variation arising from factors other than CYP1A2 activity to influence the plasma paraxanthine/caffeine ratio in mice. This study demonstrates the utility of quantitative genetics in the analysis of polygenic drug metabolism.
Footnotes
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Send reprint requests to: William L. Casley, Banting Research Centre, Tunney's Pasture 2201C, Ottawa, Ontario, Canada K1A 0L2. E-mail: Bill-Casley{at}hc-sc.gc.ca
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Presented, in part, at the 12th International Mouse Genome Conference, Garmisch-Partenkirchen, Germany, October, 1998.
- Abbreviations used are::
- CYP
- cytochrome P-450
- AHR
- aryl hydrocarbon receptor
- APN
- acetaminophen nonsusceptible
- QTL
- quantitative trait locus
- STR
- short tandem repeat
- LOD
- log-likelihood
- cM
- centiMorgan
- Received July 1, 1999.
- Accepted September 13, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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