title: Effect of oxidative stress on expression and function of human and rat organic anion transporting polypeptides in the liver.
abstract: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsujimoto
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Kaori
authors.initials: K
authors.lastname: Kuwayama
authors.forename: Takahiro
authors.initials: T
authors.lastname: Koizumi
authors.forename: Shunichi
authors.initials: S
authors.lastname: Sasaki
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Terada
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000009:adverse effects; D007288:Inosine / Q000009:adverse effects; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics*; D017035:Pravastatin / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D027361:Organic Anion Transporters; D012333:RNA, Messenger; D007288:Inosine; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D017035:Pravastatin