title: [Drug-induced hepatic injury, the challenge for cause investigation].
abstract: This report is the story of the long journey to identify the mechanism of fulminant hepatitis by the antigout drug, Benzbromarone. As soon as the 8th gout patient prescribed Benzbromarone (Benz) died of fulminant hepatitis in 20 years, the letter was sent to doctors identifying it as the causative agent in February 2000. At that time, Benz had been prescribed to 350,000 patients/year for 20 years. Is Benz the real cause of fulminant hepatitis? 1. Benz is a PPARa agonist like fenofibrate, and not a PPARgamma like troglitazone. 2. Troglitazone and Allopurinol have shown apoptosis in a human primary hepatocyte culture with the DNA laddering method, but Benz has not. 3. It was reported in 1979 that benzarone is a metabolite dissociated from two Br bases of Benz, but Walter et al. reported in 1987 that the Br base was not dissociated. Benzarone was not produced by an in vitro study with human S-9 and by an in vivo clinical study of Japanese volunteers. 4. The main metabolite of Benz in humans is 6-OH Benz, which has URAT-1 activity, like Benz. 5. It has been newly discovered that CYP2C9 is only one hepatic metabolism enzyme of Benz. 6. The rate of poor metabolizers of CYP2C9*3 (homozygous) in Japan is 1/2500, meanwhile, the rate of fulminant hepatitis at this time is 8 patients in 20 years, with 350,000 patients/year; therefore, it is difficult to view poor metabolizers as the cause. 7. Hepatic injury by Benz is an idiosyncrasy, the same as with many other drugs.
authors.affiliation: NAH00447@nifty.com
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001553:Benzbromarone / Q000009:adverse effects* / Q000494:pharmacology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002839:Chromans / Q000494:pharmacology; D006074:Gout Suppressants / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D027361:Organic Anion Transporters / Q000502:physiology; D027701:Organic Cation Transport Proteins / Q000502:physiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000502:physiology; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
chemical_list: D002839:Chromans; D006074:Gout Suppressants; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D047492:Peroxisome Proliferator-Activated Receptors; C491241:SLC22A12 protein, human; D045162:Thiazolidinediones; D001553:Benzbromarone; D000077288:Troglitazone