Species Differences in Hepatic Microsomal Coumarin Metabolism: A Role for 11β-Hydroxysteroid Dehydrogenase Type 1

Coumarin, once used as a food additive, is now widely restricted owing to risks of hepatotoxicity. Coumarin-induced hepatotoxicity is attributed to its reactive metabolite, o-hydroxyphenylacetaldehyde (o-HPA), yet the microsomal enzymes responsible for o-HPA detoxication to o-hydroxyphenylethanol (o-HPE) have not been identified. Here, we aimed to identify the key microsomal enzyme involved in o-HPA detoxication and evaluate differences in coumarin metabolism and toxicity between rats and humans. We synthesized o-HPA and assessed its microsomal metabolism and cytotoxicity in HepG2 cells. 7-Hydroxycoumarin was the dominant metabolite in human liver microsomes (HLM), whereas rat liver microsomes showed greater accumulation of o-HPA. The intrinsic clearance of o-HPA was approximately five-fold higher in HLM, indicating more efficient microsomal detoxication in humans. o-HPA exhibited higher toxicity than coumarin and its metabolites. Recombinant 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzed the reduction of o-HPA to o-HPE; 11β-HSD1 involvement was further evaluated using the inhibitor 18β-glycyrrhetinic acid. This inhibitor markedly inhibited o-HPE formation in HLM and increased coumarin-induced cytotoxicity in HepG2 cells in a dose-dependent manner. These findings identify 11β-HSD1 as a key microsomal enzyme involved in o-HPA detoxication, as well as a potential determinant of species differences in the microsomal detoxication of reactive aldehyde metabolites.