Genetic variation in the metabolism of coumarin in mouse liver

The metabolism of 50 mu M [3-C-14] coumarin to polar products separated by high performance liquid chromatography (HPLC) and covalently bound metaboli tes in liver microsomes was compared in a series of inbred strains of mice. Coumarin metabolism to total polar products was higher in female than male mice. In all strains, the coumarin 3,4-epoxidation pathway was the major r oute of metabolism with o-hydroxyphenylacetaldehyde (o-HPA) as the major me tabolite, However, in females, there was a major strain difference in the d egree of metabolism to coumarin 7-hydroxylase with DBA/2 and 129 having hig h 7-hydroxycoumarin formation, CBA/Ca having intermediate levels and the ot her strains low levels. The differences between the strains was much less p ronounced in the male mice. There was also evidence for strain variation in metabolism in the quantities of a number of other coumarin metabolites as detected by HPLC analysis of incubate extracts. However, this variation was of a quantitative nature and relatively small. The metabolism of B6C3F(1) hybrid mice, in which coumarin had been identified as carcinogenic in a lon g-term cancer bioassay, was qualitatively similar to that of the other geno types. The DBA/2 mouse has been suggested as a model for the metabolism of coumarin in humans. The pattern of metabolism found in this strain is diffe rent from most other strains. However, the pattern found for all the mouse strains, including DBA/2, differed appreciably from the profiles for other species including humans in the extent of 7-hydroxylation. Pharmacogenetics 9:239-250 (C) 1999 Lippincott Williams & Wilkins.