International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 79 - COMPARATIVE ANALYSIS OF THE NR1I3 LOCUS BETWEEN THE APN STRAIN AND A CHROMOSOME 1 APN.C3H/HEJ CONGENIC STRAIN WITH AN ALTERED DRUG METABOLISM PHENOTYPE

Casley WL, LeBlanc CA, Lavigne L, Nowakowska M

Health Canada, Ottawa, Canada

The APN mouse shows decreased capacity for caffeine metabolism relative to the C3H/HeJ mouse strain. We had previously demonstrated the presence of quantitative trait loci (QTLs) affecting 3-demethylation of caffeine on chromosomes 1, 4 and 9, using an APN x C3H/HeJ intercross. In the present study, we compare caffeine metabolism between the APN strain and a congenic strain in which the region carrying a QTL from chromosome 1 from C3H/HeJ is isolated on an APN background. The congenic interval for this strain is APN.C3H-(D1Mit495-D1Mit292). Phenotyping of the N13 generation demonstrated no significant difference for the QTL trait of caffeine 3-demethylation (p = 0.31) between the congenic and background strains, but a significant difference between the two for the trait of caffeine 7-demethylation (p = 0.003). The Nr1i3 locus, encoding the constitutive androstane receptor (CAR) lies within the congenic interval. CAR is known to regulate several Cytochrome P450 enzymes involved in drug metabolism. Hepatic expression of CAR mRNA was determined using a novel RT-PCR assay which allows the relative quantitation of both the transcript encoding the active, DNA binding form and the inactive splice variant. CAR mRNA was found to be overexpressed in APN.C3H-(D1Mit495-D1Mit292) relative to APN. Comparative sequencing of the Nr1i3 locus identified numerous SNPs as well as a 7 nucleotide insertion which may influence CAR expression.

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