Impact of the individual variance of eicosanoid disposition on the development of idiosyncratic liver injury

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15326
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Kindai University
• Principal Investigator: Shimada Hiroaki 近畿大学, 薬学部, 講師 (40783444)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: エイコサノイド / 12-HETE / PGE2 / OATP2A1 / P450 / 肝臓

Outline of Final Research Achievements

We focused to the inter-individual variance of the disposition of eicosanoids, endogenous bioactive substances, as a cause of drug toxicity that occurred with idiosyncratic manner. In this study, we aimed to clarify the regulatory mechanisms of eicosanoids disposition in the liver. We found that 12-hydrocyeicosatetraenic acid (12-HETE) is a major productive eicosanoid in rat liver and its production seems to be catalyzed by cytochrome P450 (CYP) 2C, not by lipoxygenase. Although the activity of prostaglandin E2 (PGE2) production was quite low, PGE2 was immediately disappeared in rat liver. Moreover, organic anion transporting-polypeptide (OATP) 2A1 seems to contribute to PGE2 disappearance. These results indicated that the activities of CYP2C, OATP2A1, and enzyme related to PGE2 disappearance are key factors to regulate eicosanoids disposition in liver.

Free Research Field

薬物動態学

Academic Significance and Societal Importance of the Research Achievements

特異体質性薬物性肝障害の原因として肝臓におけるエイコサノイド動態に着目したのは初めての試みである。またミクロソームなどを用いて肝組織におけるエイコサノイド産生を評価した例はあるが、肝臓の組織構造を保持したまま生体に近い条件下で肝エイコサノイド動体を評価した例は今回が初めてである。本研究成果により、肝臓におけるエイコサノイドの生成・消失に関わる分子が明らかになったことは、肝臓におけるエイコサノイド動態を変動させる因子の評価やエイコサノイド動態の変動が実際に肝障害の程度に与える影響について理解する上で意義がある。