Differential in vitro hepatotoxicity of troglitazone and rosiglitazone among cryopreserved human hepatocytes from 37 donors.
We report here our studies on troglitazone and rosiglitazone cytotoxicity in human hepatocytes isolated from multiple donors to investigate factors responsible for individual differences in sensitivity to the known hepatotoxicity of these antidiabetic drugs. Using cellular adenosine triphosphate (ATP) content as an endpoint, cytotoxicity of both drugs was evaluated in cryopreserved human hepatocytes from 37 donors. We confirmed reports of others that troglitazone was cytotoxic to human hepatocytes using cellular ATP content as an endpoint. In addition, we found that rosiglitazone, although less toxic in the study population, was cytotoxic to hepatocytes in some donors (EC(50)<100 microM). ATP content, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) metabolism, depletion of intracellular glutathione, Alamar Blue metabolism, and neutral red uptake were used as endpoints in a single donor study using freshly isolated human hepatocytes. Troglitazone appeared to be more toxic than rosiglitazone by all endpoints. From the demographic data provided to us for each donor, we were able to establish no direct correlation between cytotoxicity (expressed as EC(50) values) and age, sex, smoking status, or alcohol consumption. We conclude that troglitazone and rosiglitazone are differentially toxic to human hepatocytes, and that toxicity may be independent of age, sex, tobacco use, and alcohol use.
Lloyd
Scott
S
In Vitro Technologies, Inc., 1450 South Rolling Road, Baltimore, MD 21227, USA. lloyds@invitrotech.com
Hayden
Michael J
MJ
Sakai
Yumiko
Y
Fackett
Andrew
A
Silber
Paul M
PM
Hewitt
Nicola J
NJ
Li
Albert P
AP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000428:Alcohol Drinking; D056486:Chemical and Drug Induced Liver Injury; D002839:Chromans / Q000633:toxicity*; D004396:Coloring Agents / Q000378:metabolism; D005260:Female; D005562:Formazans / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000633:toxicity*; D007223:Infant; D008107:Liver Diseases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009499:Neutral Red / Q000378:metabolism; D010078:Oxazines; D000077154:Rosiglitazone; D012737:Sex Factors; D012907:Smoking; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000633:toxicity*; D045162:Thiazolidinediones; D000077288:Troglitazone; D014966:Xanthenes
D002839:Chromans; D004396:Coloring Agents; D005562:Formazans; D007004:Hypoglycemic Agents; D010078:Oxazines; D013778:Tetrazolium Salts; D013844:Thiazoles; D045162:Thiazolidinediones; D014966:Xanthenes; D000077154:Rosiglitazone; C005843:resazurin; C079782:MTT formazan; D009499:Neutral Red; D000255:Adenosine Triphosphate; D005978:Glutathione; D000077288:Troglitazone