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Carbamazepine is effective for the treatment of partial seizure and tonic--clonic seizure, and is one of the most commonly prescribed antiepileptic drugs [1]. Carbamazepine has a narrow therapeutic range and several adverse effects, such as hepatotoxicity, leucopenia and morbilliform rash [1,2]. Severe hepatotoxicity is rare, but mild elevations in the hepatic enzyme levels occur in 5--22% of carbamazepine-treated patients [2]. Although the mechanism behind these adverse effects is unknown, these adverse effects have been postulated to be caused by the formation of chemically reactive metabolites [2--4]. Carbamazepine is oxidized to its major metabolite carbamazepine-10,11-epoxide by cytochrome P450 (CYP) 3A, and is metabolized to more than 30 additional metabolites in humans [2,5,6]. The representative candidates for the etiologic metabolites of the adverse effects are carbamazepine-10,11-epoxide, carbamazepine arene oxide(s) and carbamazepine iminoquinone(s), and they are detoxified by glutathione S -transferase (GST) and microsomal epoxide hydrolase (mEH) [2,3,7,8]. It is therefore conceivable that some functional polymorphisms in the genes encoding these enzymes may thus pose an increased risk for the adverse effects of carbamazepine.
GSTs comprise a supergene family of enzymes and catalyze the detoxification of a variety of reactive compounds, chemicals and their metabolites [9,10]. GSTM1 and GSTT1 are predominantly expressed in the liver and display polymorphisms in humans [9,10]. The GSTM1 and GSTT1 deficiencies, caused by a homozygous deletion of the gene (null genotype), are present in approximately 50 ±± 5% and 45 ±± 5% of Japanese, respectively [9,11,12]. mEH catalyzes the trans-addition of water to a broad range of epoxide substrates, such as reactive epoxide intermediates [13]. The major polymorphisms of the mEH coding region are mEH-3 , the substitution of 113 tyrosine (Tyr) to histidine (His) at exon 3, and mEH-4 , the substitution of 139 His to arginine (Arg) at exon 4 [13,14].
Most drug-induced liver injuries in humans are unpredictable and poorly understood. Although the occurrence ranges between 1 in 10,000 and 1 in 100,000 patients [15], drug-induced liver injury is the leading cause of acute liver failure in the USA, accounting for approximately half of all cases [16]. The case of troglitazone, which was withdrawn from the market in March 2000 because of its association with idiosyncratic hepatotoxicity, highlighted the need to better appreciate the signals that could potentially predict...