Troglitazone enhances the hepatotoxicity of acetaminophen by inducing CYP3A in rats.
Troglitazone (TRZ) is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is proven to lower plasma glucose levels in patients with type 2 diabetes mellitus. However, the concern has been raised because of several reports, in which severe hepatic dysfunction leading to hepatic failure was demonstrated in a few patients receiving the drug. We studied the effects of TRZ on the hepatotoxicity of carbon tetrachloride (CCl(4)) and acetaminophen (APAP) in rats, both of which exert their toxic effects through bioactivation associated with cytochrome P450 3A (CYP3A) and 2E1 (CYP2E1). Male standard (Wistar/ST) and type 2 diabetic model (GK/Jal) rats were kept on a powdered chow diet containing 0, 100, 500 mg/kg/rat of TRZ. Three weeks later, the rats were either sacrificed for an in vitro metabolism study or challenged with 0.50 g/kg CCl(4) p.o. or 0.75 g/kg APAP i.p.TRZ at 100 and 500 mg/kg/rat increased the CYP3A level as well as the testosterone 6beta-hydroxylation activities in liver microsomes, but did not affect CYP2E1. TRZ also enhanced APAP hepatotoxicity, as evidenced by significantly increased levels of alanine aminotransferase, aspartate aminotransferase and alpha-glutathione S-transferase in the plasma of rats, and by significantly low hepatic glutathione concentration. Our study demonstrated that high doses of TRZ can enhance hepatotoxicity of APAP in Wistar/ST and GK/Jal by inducing hepatic CYP3A.
Li
Jue
J
Department of Environmental Health, Medical University of Yamanashi, Yamanashi Tamaho 409-3898, Japan.
Kaneko
Takashi
T
Wang
Yuan
Y
Qin
Li-Qiang
LQ
Wang
Pei-Yu
PY
Sato
Akio
A
D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D002839:Chromans / Q000008:administration & dosage / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D000077288:Troglitazone