Biliary excretion of tauroursodeoxycholate-3-sulfate in the rat

Akimoto, Kazuko; Sano, Naoyo; Takikawa, Hajime

doi:10.1016/s0039-128x(01)00102-7

Cited by 1 publication

(1 citation statement)

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“…Therefore, BCRP is the major transporter involved in the biliary excretion of TGZS. Cumulative studies using Mrp2-deficient mutant rats have shown that MRP2 accounts for the biliary excretion of some sulfate conjugates, such as tauro-conjugated bile acid sulfate, phenolphthalein sulfate, and acetaminophen sulfate (Takikawa et al, 1991;Akimoto et al, 2001;Tanaka et al, 2003;Zamek-Gliszczynski et al, 2005). Very recently, Zamek-Gliszczynski et al (2006) showed that BCRP is also involved in the biliary excretion of sulfate conjugates, including 4-methylumbelliferone sulfate, acetaminophen sulfate, and harmol sulfate, using Bcrp (Ϫ/Ϫ) mice.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Breast Cancer Resistance Protein (BCRP/ABCG2) in the Biliary Excretion and Intestinal Efflux of Troglitazone Sulfate, the Major Metabolite of Troglitazone with a Cholestatic Effect

Enokizono

Kusuhara²,

Sugiyama³

2006

Drug Metab Dispos

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ABSTRACT:Troglitazone sulfate (TGZS) is the major metabolite of troglitazone (TGZ), an antidiabetic agent, and thought to be a cause of the cholestasis induced by TGZ. The aim of the present study is to elucidate the involvement of breast cancer resistance protein (BCRP/ABCG2) in the hepatic disposition of TGZS. The basal-toapical transport of TGZS was enhanced in organic anion transporting polypeptide 1B1-expressing Madin-Darby canine kidney II cells by infection of recombinant adenovirus harboring human BCRP and mouse Bcrp cDNA. TGZS was given to wild-type and Bcrp (؊/؊) mice by constant infusion. Biliary excretion is the predominant elimination pathway of TGZS in wild-type mice, and the biliary excretion clearance of TGZS with regard to the hepatic concentration was reduced to 30% of the control in Bcrp (؊/؊) mice. However, plasma and hepatic concentrations were unchanged, suggesting induction of compensatory mechanisms in Bcrp (؊/؊) mice for the elimination of TGZS. Involvement of BCRP in the intestinal efflux transport of TGZS was examined using everted sacs. The mucosal efflux clearance of TGZS showed only a slight reduction (15% reduction) in Bcrp (؊/؊) mice. Our results suggest that BCRP plays a major role in the biliary excretion but a minor role in the intestinal transport of TGZS.Troglitazone (TGZ) (Fig. 1a) was the first marketed thiazolidinedione, and it has been used for the treatment of type 2 hyperglycemia. It can sensitize tissues to insulin by activating peroxisome proliferator-activated receptor-␥, thereby inhibiting glucose release from hepatocytes and enhancing the insulin-dependent glucose metabolism in adipose tissue and skeletal muscle (reviewed in Chen, 1998). However, TGZ was withdrawn from the market in 2000 because of idiosyncratic severe hepatotoxicity. A great deal of research was carried out on the hepatotoxicity of TGZ, and multiple mechanisms were proposed, such as the production of reactive intermediates and direct mitochondrial injury (reviewed in Smith, 2003). An alternative mechanism that has been proposed is cholestasis. Cholestasis was observed in patients with severe hepatotoxicity (Fukano et al., 2000;Menon et al., 2001), andFunk et al. (2001b) showed that a single bolus administration of TGZ increased the plasma bile acid concentration in rats. Because troglitazone sulfate (TGZS) (Fig. 1b), the major metabolite of TGZ, is a more potent inhibitor of the bile salt export pump (BSEP) than TGZ, and the hepatic concentration of TGZS was much greater than that of TGZ (Funk et al., 2001b), TGZS has been hypothesized to account for the cholestatic effect of TGZ. A gender difference in the cholestatic effect of TGZ in rats was related to the sex-dependent formation of TGZS: the formation of TGZS was greater in male rats, which exhibit more severe cholestasis (Funk et al., 2001a). Based on these findings, it has been speculated that TGZS increases the likelihood of hepatotoxicity induced by TGZ. In addition to the conjugation rate, the hepatic elimination mechanism of TGZS will be...

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Section: Discussionmentioning

confidence: 99%