Kengo Sakurai, Tomohiro Kuroda, Jun Abe, Hiroshi Toda, Sachiko Kitamoto
Pharmacology research & perspectives 2021 OctEpyrifenacil is a novel herbicide that acts as an inhibitor of protoporphyrinogen oxidase (PPO) and produces hepatotoxicity in rodents by inhibiting PPO. Our previous research revealed that the causal substance of hepatotoxicity is S-3100-CA, a major metabolite of epyrifenacil, and that human hepatocyte uptake of S-3100-CA was significantly lower than rodent one, suggesting less relevant to hepatotoxicity in humans. To clarify the species difference in the uptake of S-3100-CA, we focused on organic anion transporting polypeptides (OATPs) and carried out an uptake assay using human, rat, and mouse OATP hepatic isoforms-expressing 293FT cells. As a result, all the examined OATPs were found to contribute to the S-3100-CA uptake, suggesting that the species difference was not due to the differences in selectivity toward OATP isoforms. When [14 C]epyrifenacil was administered to mice, the liver concentration of S-3100-CA was higher in males than in females. Furthermore, when [14 C]epyrifenacil was administered with OATP inhibitors, the liver/plasma ratio of S-3100-CA was significantly decreased by rifampicin, an Oatp1a1/Oatp1a4 inhibitor in mice, but not by digoxin, an Oatp1a4-specific inhibitor. This result indicates that Oatp1a1, the predominant transporter in male mice, is the main contributor to the hepatic transport of S-3100-CA, and consequently to the gender difference. Moreover, we conclude that the species difference in the hepatic uptake of S-3100-CA observed in our previous research is not due to differences in the selectivity toward OATP isoforms but rather to the significantly higher expression of OATPs which mediate uptake of S-3100-CA in rodents than in humans. © 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.
Kengo Sakurai, Tomohiro Kuroda, Jun Abe, Hiroshi Toda, Sachiko Kitamoto. Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S-3100-CA, in mice. Pharmacology research & perspectives. 2021 Oct;9(5):e00877
PMID: 34619012
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