A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus.
OBJECTIVE
Troglitazone is a 2,4-thiazolidinedione antidiabetic agent with insulin-sensitizing activities. This agent had been used efficiently in a large number of patients but was withdrawn from the market in March 2000 because of its association with idiosyncratic hepatotoxicity. To address the susceptible genetic factors responsible for the hepatotoxicity associated with this agent, we performed a genetic polymorphic analysis by a target gene approach in troglitazone-treated Japanese patients with type 2 diabetes mellitus.


METHODS
One hundred ten patients treated with troglitazone were recruited into this study. The case patients (n = 25) were recruited through medical professionals who had previously reported abnormal increases in the levels of ALT or AST among their patients. The control patients (n = 85) were recruited through physicians prescribing troglitazone. For statistical accuracy, efforts were made to maximize the size of the case group. Genotype analysis was performed in 68 polymorphic sites of 51 candidate genes related to drug metabolism, apoptosis, roduction and elimination of reactive oxygen species, and signal transduction pathways of peroxisome proliferator-activated receptor gamma 2 and insulin.


RESULTS
The strong correlation with transaminase elevations was observed in the combined glutathione-S-transferase GSTT1-GSTM1 null genotype (odds ratio, 3.692; 95% confidence interval, 1.354-10.066; P =.008).


CONCLUSIONS
The double null mutation of GSTT1 and GSTM1 might influence troglitazone-associated abnormal increases of liver enzyme levels.
Regulatory Affairs Department, Sankyo Co, Ltd, Tokyo, Japan.
Ichiro
I
Watanabe
Aiko
A
Tomita
Miho
M
Shimizu
Mie
M
Sugawara
Hiroaki
H
Yasumo
Ryuta
R
Koishi
Tohru
T
Takahashi
Kaoru
K
Miyoshi
Kouichi
K
Nakamura
Takashi
T
Izumi
Yasuyuki
Y
Matsushita
Hidehiko
H
Furukawa
Hideyuki
H
Haruyama
Teiichiro
T
Koga
D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000483:Alleles; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications* / Q000453:epidemiology / Q000235:genetics*; D002839:Chromans / Q000009:adverse effects*; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D003625:Data Collection; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D012727:Sex Characteristics; D013844:Thiazoles / Q000009:adverse effects*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D017931:DNA Primers; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D004247:DNA; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077288:Troglitazone