Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: Implications for understanding troglitazone hepatotoxicity

被引:78
作者
Nozawa, T
Sugiura, S
Nakajima, M
Goto, A
Yokoi, T
Nezu, JI
Tsuji, A
Tamai, I
机构
[1] Sci Univ Tokyo, Fac Pharmaceut Sci, Dept Mol Biopharmaceut, Noda, Chiba 2788510, Japan
[2] Kanazawa Univ, Fac Pharmaceut Sci, Kanazawa, Ishikawa 920, Japan
[3] Nara Med Univ, Med Genet Res Ctr, Nara, Japan
[4] Chugai Pharmaceut Co Ltd, Tsukuba, Ibaraki, Japan
关键词
D O I
10.1124/dmd.32.3.291
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Troglitazone is a thiazolidinedione insulin sensitizer drug that is metabolized mainly to a sulfate conjugate (M-1) in humans. It was reported to cause hepatotoxicity, although the cause has not been fully clarified. The objective of this study was to identify whether organic anion transporting polypeptide (OATP) transporters expressed at the basolateral membrane of human hepatocytes participate in troglitazone-associated hepatotoxicity. When OATP-B, OATP-C, or OATP8 was expressed in Xenopus oocytes, the transporter-mediated uptake into oocytes of troglitazone sulfate conjugate and the inhibitory effects of thiazolidinediones and the metabolites of troglitazone on estrone-3-sulfate transport were measured. M-1 was transported well by OATP-C but was not transported by OATP-B. OATP8 showed weak, but not statistically significant, transport of M-1. M-1 exhibited a strong inhibitory effect on estrone-3-sulfate transport by OATP-C and OATP8, suggesting a higher affinity than other thiazolidinediones and the metabolites of troglitazone, glucuronide conjugate and quinone metabolite. In conclusion, the sulfate conjugate of troglitazone has a higher affinity for OATPs than troglitazone itself or other metabolites. Since OATP transporters are important in the hepatic handling of bile acids, bilirubin, and other endogenous anionic compounds, M-1 may disturb the hepatic influx and efflux transport of these endogenous molecules across the basolateral membranes. Moreover, OATP-C may be involved in the hepatic toxicity of troglitazone through the inhibitory action of M-1.
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页码:291 / 294
页数:4
相关论文
共 18 条
[1]   Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: In vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat [J].
Funk, C ;
Ponelle, C ;
Scheuermann, G ;
Pantze, M .
MOLECULAR PHARMACOLOGY, 2001, 59 (03) :627-635
[2]   Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone [J].
Gitlin, N ;
Julie, NL ;
Spurr, CL ;
Lim, KN ;
Juarbe, HM .
ANNALS OF INTERNAL MEDICINE, 1998, 129 (01) :36-38
[3]   The superfamily of organic anion transporting polypeptides [J].
Hagenbuch, B ;
Meier, PJ .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2003, 1609 (01) :1-18
[4]   Intestinal absorption and excretion of troglitazone sulphate, a major biliary metabolite of troglitazone [J].
Kawai, K ;
Hirota, T ;
Muramatsu, S ;
Tsuruta, F ;
Ikeda, T ;
Kobashi, K ;
Nakamura, KI .
XENOBIOTICA, 2000, 30 (07) :707-715
[5]  
Kawai K, 1997, ARZNEIMITTEL-FORSCH, V47, P356
[6]  
Kostrubsky VE, 2000, DRUG METAB DISPOS, V28, P1192
[7]  
Kostrubsky VE, 2001, DRUG METAB DISPOS, V29, P1561
[8]   Lack of effect of type II diabetes on the pharmacokinetics of troglitazone in a multiple-dose study [J].
Loi, CM ;
Randinitis, EJ ;
Vassos, AB ;
Kazierad, DJ ;
Koup, JR ;
Sedman, AJ .
JOURNAL OF CLINICAL PHARMACOLOGY, 1997, 37 (12) :1114-1120
[9]   Clinical pharmacokinetics of troglitazone [J].
Loi, CM ;
Young, M ;
Randinitis, E ;
Vassos, A ;
Koup, JR .
CLINICAL PHARMACOKINETICS, 1999, 37 (02) :91-104
[10]   A naturally occurring mutation in the SLC21A6 gene causing impaired membrane localization of the hepatocyte uptake transporter [J].
Michalski, C ;
Cui, YH ;
Nies, AT ;
Nuessler, AK ;
Neuhaus, P ;
Zanger, UM ;
Klein, K ;
Eichelbaum, M ;
Keppler, D ;
König, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (45) :43058-43063