Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice

Abstract Epyrifenacil 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 hum...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kengo Sakurai, Tomohiro Kuroda, Jun Abe, Hiroshi Toda, Sachiko Kitamoto
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	active hepatic uptake epyrifenacil gender difference herbicide species difference OATP Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/7a3eacb68306478f8d36c9eaa9956cf8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:7a3eacb68306478f8d36c9eaa9956cf8
record_format	dspace
spelling	oai:doaj.org-article:7a3eacb68306478f8d36c9eaa9956cf82021-11-16T13:45:55ZIdentification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice2052-170710.1002/prp2.877https://doaj.org/article/7a3eacb68306478f8d36c9eaa9956cf82021-10-01T00:00:00Zhttps://doi.org/10.1002/prp2.877https://doaj.org/toc/2052-1707Abstract Epyrifenacil 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 [14C]epyrifenacil was administered to mice, the liver concentration of S‐3100‐CA was higher in males than in females. Furthermore, when [14C]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.Kengo SakuraiTomohiro KurodaJun AbeHiroshi TodaSachiko KitamotoWileyarticleactive hepatic uptakeepyrifenacilgender differenceherbicidespecies differenceOATPTherapeutics. PharmacologyRM1-950ENPharmacology Research & Perspectives, Vol 9, Iss 5, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	active hepatic uptake epyrifenacil gender difference herbicide species difference OATP Therapeutics. Pharmacology RM1-950
spellingShingle	active hepatic uptake epyrifenacil gender difference herbicide species difference OATP Therapeutics. Pharmacology RM1-950 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
description	Abstract Epyrifenacil 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 [14C]epyrifenacil was administered to mice, the liver concentration of S‐3100‐CA was higher in males than in females. Furthermore, when [14C]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.
format	article
author	Kengo Sakurai Tomohiro Kuroda Jun Abe Hiroshi Toda Sachiko Kitamoto
author_facet	Kengo Sakurai Tomohiro Kuroda Jun Abe Hiroshi Toda Sachiko Kitamoto
author_sort	Kengo Sakurai
title	Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice
title_short	Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice
title_full	Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice
title_fullStr	Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice
title_full_unstemmed	Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice
title_sort	identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, s‐3100‐ca, in mice
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/7a3eacb68306478f8d36c9eaa9956cf8
work_keys_str_mv	AT kengosakurai identificationoftheorganicaniontransportingpolypeptidesresponsibleforthehepaticuptakeofthemajormetaboliteofepyrifenacils3100cainmice AT tomohirokuroda identificationoftheorganicaniontransportingpolypeptidesresponsibleforthehepaticuptakeofthemajormetaboliteofepyrifenacils3100cainmice AT junabe identificationoftheorganicaniontransportingpolypeptidesresponsibleforthehepaticuptakeofthemajormetaboliteofepyrifenacils3100cainmice AT hiroshitoda identificationoftheorganicaniontransportingpolypeptidesresponsibleforthehepaticuptakeofthemajormetaboliteofepyrifenacils3100cainmice AT sachikokitamoto identificationoftheorganicaniontransportingpolypeptidesresponsibleforthehepaticuptakeofthemajormetaboliteofepyrifenacils3100cainmice
_version_	1718426488268652544

Identification of the organic anion transporting polypeptides responsible for the hepatic uptake of the major metabolite of epyrifenacil, S‐3100‐CA, in mice

Ejemplares similares