Glutathione S-transferase M1 null genotype as a risk factor for carbamazepine-induced mild hepatotoxicity.
The aim of this study is to verify whether the combination of glutathione S-transferase (GST) M1 null and GSTT1 null genotypes, which is a candidate genetic risk factor for troglitazone-induced liver failure, is common to that for the carbamazepine-induced mild hepatotoxicity.


METHODS
The genotypes of GSTM1 and GSTT1, and microsomal epoxide hydrolase-3 and -4, were determined in 192 Japanese epileptics treated with carbamazepine.


RESULTS
The GSTM1 null (GSTM1-) and GSTT1 null (GSTT1-) genotypes in the subjects were 55.7 and 39.6%, respectively. The alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were elevated in 46 (24.0%) and 62 (32.3%) cases, and the mean values were approximately 2.3- and 1.8-times higher than the upper limit of normal levels, respectively. The levels of ALT and AST were significantly higher in GSTM1- than in GSTM1 present (GSTM1+) genotypes (p = 0.007 and 0.004, respectively). The level of ALT was significantly higher in GSTM1-/T1- than in GSTM1+/T1- and GSTM1+/T1+ (p = 0.01 and 0.01, respectively), and that of AST was significantly higher in GSTM1-/T1- and GSTM1-/T1+ than in GSTM1+/T1+ (p = 0.02 and 0.003, respectively). The microsomal epoxide hydrolase genotype did not influence the hepatotoxicity.


CONCLUSIONS
These findings suggested that GSTM1- rather than GSTM1-/T1- was a risk factor for carbamazepine-induced mild hepatotoxicity.
Ueda
Kentaro
K
Kumamoto University, Division of Pharmacology and Therapeutics, Graduate School of Medical and Pharmaceutical Science, Oe-honmachi 5-1, Kumamoto 862-0973, Japan.
Ishitsu
Takateru
T
Seo
Takayuki
T
Ueda
Nao
N
Murata
Tsukasa
T
Hori
Masaharu
M
Nakagawa
Kazuko
K
D000293:Adolescent; D000927:Anticonvulsants / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D002220:Carbamazepine / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D008969:Molecular Sequence Data; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D012720:Severity of Illness Index
D000927:Anticonvulsants; D002220:Carbamazepine; D005982:Glutathione Transferase