Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver

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• 作者：Takashi Tsujimoto ; Jiro Ogura ; Kaori Kuwayama ; Takahiro Koizumi ; Shunichi Sasaki ; Yusuke Terada ; Masaki Kobayashi ; Hiroaki Yamaguchi ; Ken Iseki
• 关键词：Organic anion transporting polypeptide ; Hydrogen peroxide ; Oxidative stress ; Pharmacokinetics
• 刊名：International Journal of Pharmaceutics
• 出版年：31 December, 2013
• 年：2013
• 卷：458
• 期：2
• 页码：262-271
• 全文大小：1113 K

文摘

Reactive oxygen species (ROS) have physiological function and involve alteration of physical state. However, it is not clear effect of oxidative stress on pharmacokinetics. Organic anion transporting polypeptides (human: OATPs, rodent: Oatps) are important for uptake of endogenous and exogenous compounds into hepatocytes. Thus, alteration of OATPs/Oatps expression level may affect pharmacokinetics of various drugs. In this study, we investigated the alteration of OATPs/Oatps expression levels and function by oxidative stress, and the effect of alteration of those on pharmacokinetics of a typical OATPs/Oatps substrate pravastatin. OATPs/Oatps expression levels and function were altered by H₂O₂-induced oxidative stress in in vitro experiments. The alteration of Oatps expression by oxidative stress also occurred in in vivo experiments. Oatp1a1, Oatp1a4 and Oatp1b2 expression in the liver were decreased in rats fed powdery diet containing 2% inosine, which induces oxidative stress through activation of xanthine oxidase, for 1 day. The decrease in Oatps expression levels by oxidative stress caused the suppression of pravastatin uptake to the liver, and resulted in high plasma concentration of pravastatin and low biliary excretion. In conclusion, oxidative stress induces alteration of OATPs/Oatps expression and function in hepatocytes, resulting in alteration of pharmacokinetics of their substrates.