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

Takashi Yamada; Naruo Katsutani; Taeko Maruyama; Tomoko Kawamura; Hiroshi Yamazaki; Norie Murayama; Weida Tong; Yasushi Yamazoe; Akihiko Hirose

doi:10.14252/foodsafetyfscj.D-21-00015

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

Food Saf (Tokyo). 2022 Sep 23;10(3):73-82. doi: 10.14252/foodsafetyfscj.D-21-00015. eCollection 2022 Sep.

Authors

Takashi Yamada¹, Naruo Katsutani¹, Taeko Maruyama¹, Tomoko Kawamura¹, Hiroshi Yamazaki², Norie Murayama², Weida Tong³, Yasushi Yamazoe^{1

4}, Akihiko Hirose¹

Affiliations

¹ Division of Risk Assessment, Center for Biological Safety Research, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki 210-9501, Japan.
² Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan.
³ National Center for Toxicological Research, Food and Drug Administration, 3900 NCTR Road, Jefferson, AR 72079, United States of America.
⁴ Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan.

Abstract

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.

Keywords: coumarin; drug-induced liver injury score model; hepatotoxicity; individual susceptibilities; physiologically based pharmacokinetics.