Combined Risk Assessment of Food-derived Coumarin with in Silico Approaches.

Hepatotoxicity associated with food-derived coumarin occurs occasionally in humans. We have, herein, assessed the data of existing clinical and nonclinical studies as well as those of in silico models for humans in order to shed more light on this association. The average intakes of food-derived coumarin are estimated to be 1-3 mg/day, while a ten-times higher level is expected in the worst-case scenarios. These levels are close to or above the tolerable daily intake suggested by a chronic study in dogs. The human internal exposure levels were estimated by a physiologically-based pharmacokinetic model with the use of virtual doses of coumarin in the amounts expected to derive from foods. Our results suggest that: (i) coumarin can be cleared rapidly via 7-hydroxylation in humans, and (ii) the plasma levels of coumarin and of its metabolite, o-hydroxyphenylacetic acid associated with hepatotoxicity, are considerably lower than those yielding hepatotoxicity in rats. Pharmacokinetic data suggest a low or negligible concern regarding a coumarin-induced hepatotoxicity in humans exposed to an average intake from foods. Detoxification of coumarin through the 7-hydroxylation, however, might vary among individuals due to genetic polymorphisms in CYP2A6 enzyme. In addition, the CYP1A2- and CYP2E1-mediated activation of coumarin can fluctuate as a result of induction caused by environmental factors. Furthermore, the daily consumption of food-contained coumarin was implicated in the potential risk of hepatotoxicity by the drug-induced liver injury score model developed by the US Food and Drug Administration. These results support the idea of the existence of human subpopulations that are highly sensitive to coumarin; therefore, a more precise risk assessment is needed. The present study also highlights the usefulness of in silico approaches of pharmacokinetics with the liver injury score model as battery components of a risk assessment.