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Vol. 30, Issue 8, 944-949, August 2002

Phenol Sulfotransferase, ST1A3, as the Main Enzyme Catalyzing Sulfation of Troglitazone in Human Liver

Wataru Honma, Miki Shimada, Hironobu Sasano, Shogo Ozawa, Masaaki Miyata, Kiyoshi Nagata, Toshihiko Ikeda, and Yasushi Yamazoe

Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (W.H., M.S., M.M., K.N., and Y.Y.); Department of Anatomic Pathology, School of Medicine, Tohoku University, Sendai, Japan (H.S.); Division of Pharmacology, National Institute of Health Sciences, Tokyo, Japan (S.O.); and Pharmacokinetics and Drug Delivery Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan (T.I.)

Since sulfation is the main metabolic pathway of troglitazone, accounting for about 70% of the metabolites detected in human plasma, we have aimed to identify human cytosolic sulfotransferases catalyzing the sulfation of troglitazone and to examine a possible role of the sulfation in the cytotoxicity observed in cell lines of human origin (HepG2 and Hep3B). Experiments using the recombinant sulfotransferases and human liver cytosols indicated that phenol sulfotransferase (ST1A3) and estrogen sulfotransferase (ST1E4) were the sulfotransferases most active toward troglitazone. Immunoblot analyses indicated that hepatic content of ST1A3 is about 13 times higher than that of ST1E4, suggesting that ST1A3 is mainly responsible for the sulfation of troglitazone in the liver. Lactate dehydrogenase (LDH) leakage was elicited by troglitazone in a concentration-dependent manner in the hepatoma cells. The troglitazone metabolites (the sulfate, glucuronide, and quinone forms) caused negligible LDH leakage. These findings suggest that accumulation of unmetabolized troglitazone causes the cytotoxicity in the hepatoma cells and may be responsible for toxicity in human liver.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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