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

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-to-apical 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.

[1]  K. Brouwer,et al.  MULTIPLE MECHANISMS ARE INVOLVED IN THE BILIARY EXCRETION OF ACETAMINOPHEN SULFATE IN THE RAT: ROLE OF MRP2 AND BCRP1 , 2005, Drug Metabolism and Disposition.

[2]  T. Kinoshita,et al.  Disposition and metabolism of the new oral antidiabetic drug troglitazone in rats, mice and dogs. , 1997, Arzneimittel-Forschung.

[3]  Kim L R Brouwer,et al.  The Important Role of Bcrp (Abcg2) in the Biliary Excretion of Sulfate and Glucuronide Metabolites of Acetaminophen, 4-Methylumbelliferone, and Harmol in Mice , 2006, Molecular Pharmacology.

[4]  C. Woodworth,et al.  Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment , 2005, Molecular Cancer Therapeutics.

[5]  A. V. van Herwaarden,et al.  The Breast Cancer Resistance Protein (BCRP/ABCG2) Affects Pharmacokinetics, Hepatobiliary Excretion, and Milk Secretion of the Antibiotic Nitrofurantoin , 2005, Molecular Pharmacology.

[6]  Yuichi Sugiyama,et al.  Role of Breast Cancer Resistance Protein (Bcrp1/Abcg2) in the Extrusion of Glucuronide and Sulfate Conjugates from Enterocytes to Intestinal Lumen , 2005, Molecular Pharmacology.

[7]  H. Takikawa,et al.  Biliary Excretion of Phenolphthalein Sulfate in Rats , 2003, Pharmacology.

[8]  T. Dale,et al.  The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk , 2005, Nature Medicine.

[9]  H. Sasano,et al.  Phenol sulfotransferase, ST1A3, as the main enzyme catalyzing sulfation of troglitazone in human liver. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[10]  Steffen Bauer,et al.  Evidence for Inverse Effects of OATP‐C (SLC21A6) *5 and *1b Haplotypes on Pravastatin Kinetics , 2004, Clinical pharmacology and therapeutics.

[11]  M. Oshimura,et al.  FUNCTIONAL ASSESSMENT OF ABCG2 (BCRP) GENE POLYMORPHISMS TO PROTEIN EXPRESSION IN HUMAN PLACENTA , 2005, Drug Metabolism and Disposition.

[12]  C. Funk,et al.  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. , 2001, Molecular pharmacology.

[13]  L. Ranek,et al.  Pharmacokinetics of troglitazone, a PPAR-γ agonist, in patients with hepatic insufficiency , 1998, European Journal of Clinical Pharmacology.

[14]  J. Verweij,et al.  Effect of ABCG2 genotype on the oral vioavailability of topotecan , 2005, Cancer biology & therapy.

[15]  B. Paigen,et al.  Genetic factors at the enterocyte level account for variations in intestinal cholesterol absorption efficiency among inbred strains of mice. , 2001, Journal of lipid research.

[16]  H. Takikawa,et al.  Biliary excretion of tauroursodeoxycholate-3-sulfate in the rat , 2001, Steroids.

[17]  J. Nezu,et al.  Involvement of organic anion transporting polypeptides in the transport of troglitazone sulfate: implications for understanding troglitazone hepatotoxicity. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[18]  H. van Goor,et al.  Fat malabsorption in essential fatty acid-deficient mice is not due to impaired bile formation. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[19]  H. Kusuhara,et al.  Impaired renal excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) sulfate in breast cancer resistance protein (BCRP1/ABCG2) knockout mice. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[20]  Martyn T. Smith,et al.  Mechanisms of troglitazone hepatotoxicity. , 2003, Chemical research in toxicology.

[21]  Jos H Beijnen,et al.  The breast cancer resistance protein (Bcrp1/Abcg2) restricts exposure to the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. , 2003, Cancer research.

[22]  Kazuya Maeda,et al.  Identification of the Hepatic Efflux Transporters of Organic Anions Using Double-Transfected Madin-Darby Canine Kidney II Cells Expressing Human Organic Anion-Transporting Polypeptide 1B1 (OATP1B1)/Multidrug Resistance-Associated Protein 2, OATP1B1/Multidrug Resistance 1, and OATP1B1/Breast Cancer R , 2005, Journal of Pharmacology and Experimental Therapeutics.

[23]  Yuichi Sugiyama,et al.  Lack of Improvement of Oral Absorption of ME3277 by Prodrug Formation Is Ascribed to the Intestinal Efflux Mediated by Breast Cancer Resistant Protein (BCRP/ABCG2) , 2005, Pharmaceutical Research.

[24]  Yuichi Sugiyama,et al.  ABCG2 Transports Sulfated Conjugates of Steroids and Xenobiotics* , 2003, Journal of Biological Chemistry.

[25]  L. Ranek,et al.  Pharmacokinetics of troglitazone, a PPAR-gamma agonist, in patients with hepatic insufficiency. , 1998, European journal of clinical pharmacology.

[26]  Y. Sugiyama,et al.  Functional Analysis of SNPs Variants of BCRP/ABCG2 , 2004, Pharmaceutical Research.

[27]  T. Mikami,et al.  Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant sprague‐dawley rat , 1991, Hepatology.

[28]  M. J. van de Vijver,et al.  Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. , 2001, Cancer research.

[29]  Y. Miki,et al.  C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. , 2002, Molecular cancer therapeutics.

[30]  Sharon Marsh,et al.  Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype , 2004, Clinical pharmacology and therapeutics.

[31]  K. Yamamoto,et al.  Subacute hepatic failure associated with a new antidiabetic agent, troglitazone: a case report with autopsy examination. , 2000, Human pathology.

[32]  K. Maeda,et al.  Effects of organic anion transporting polypeptide 1B1 haplotype on pharmacokinetics of pravastatin, valsartan, and temocapril , 2006, Clinical pharmacology and therapeutics.

[33]  R. Weinshilboum,et al.  Phenol sulfotransferase pharmacogenetics in humans: association of common SULT1A1 alleles with TS PST phenotype. , 1997, Biochemical and biophysical research communications.

[34]  S. Muramatsu,et al.  Intestinal absorption and excretion of troglitazone sulphate, a major biliary metabolite of troglitazone , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[35]  K. Lindor,et al.  Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus , 2001, American Journal of Gastroenterology.

[36]  L. Skoog,et al.  Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients , 2005, Breast Cancer Research.

[37]  C. Chen.  Troglitazone: an antidiabetic agent. , 1998, American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists.

[38]  M. Vore,et al.  The effect of troglitazone biliary excretion on metabolite distribution and cholestasis in transporter-deficient rats. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[39]  H. Rosing,et al.  The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  L. Hutchins,et al.  Association between sulfotransferase 1A1 genotype and survival of breast cancer patients receiving tamoxifen therapy. , 2002, Journal of the National Cancer Institute.

[41]  Yuichi Sugiyama,et al.  Polymorphisms of OATP‐C (SLC21A6) and OAT3 (SLC22A8) genes: Consequences for pravastatin pharmacokinetics , 2003, Clinical pharmacology and therapeutics.

[42]  Ya-li Liu,et al.  Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[43]  K. Maeda,et al.  Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin , 2005, Molecular Pharmacology.