Fukushima Yumi, Seo Takayuki, Hashimoto Nami, Higa Yoko, Ishitsu Takateru, Nakagawa Kazuko
Pharmaceutical Division, F Hoffmann-La Roche Ltd, Basel, Switzerland.
Clin Chim Acta. 2008 Mar;389(1-2):98-102. doi: 10.1016/j.cca.2007.11.035. Epub 2007 Dec 7.
This study was designed to verify whether the glutathione S-transferase (GST) genotypes affect mild hepatotoxicity in valproic acid (VPA)-treated patients.
The association between the GSTM1 and GSTT1 genotypes, and the levels of aminotransferases and total bilirubin was retrospectively investigated in 149 Japanese epileptic patients treated with VPA.
The adjusted odds ratio (OR) of the GSTM1- vs. GSTM1+ genotype and the GSTM1-/GSTT1-vs. GSTM1+/GSTT1+ genotypes for gamma-glutamyltransferase (GGT) increase over the upper limit of normal were 2.8 [95% confidence interval (CI): 1.1-7.2] and 6.5 (95% CI: 1.5-28.0), respectively. The GSTT1 genotypes alone did not significantly affect the liver function tests. The alanine aminotransferase, aspartate aminotransferase and (gamma-glutamyltransferase) GGT levels in patients treated with VPA >6 months were significantly higher in the GSTM1- than GSTM1+ genotype. The GGT levels were significantly higher in the older subjects receiving polytherapy, and the effects of the polytherapy and age were greater in the GSTM1- genotype.
The GSTM1- and GSTM1-/GSTT1- genotypes may be a genetic risk factor for the increase of GGT in VPA-treated patients. However, it was not possible to clarify whether the GGT increase was caused by VPA-induced hepatotoxicity or not.
本研究旨在验证谷胱甘肽S-转移酶(GST)基因型是否会影响丙戊酸(VPA)治疗患者的轻度肝毒性。
回顾性调查了149例接受VPA治疗的日本癫痫患者的GSTM1和GSTT1基因型与转氨酶和总胆红素水平之间的关联。
GSTM1-基因型与GSTM1+基因型相比,以及GSTM1-/GSTT1-基因型与GSTM1+/GSTT1+基因型相比,γ-谷氨酰转移酶(GGT)升高超过正常上限的校正比值比(OR)分别为2.8 [95%置信区间(CI):1.1-7.2]和6.5(95%CI:1.5-28.0)。单独的GSTT1基因型对肝功能检查无显著影响。接受VPA治疗>6个月的患者中,GSTM1-基因型患者的丙氨酸转氨酶、天冬氨酸转氨酶和(γ-谷氨酰转移酶)GGT水平显著高于GSTM1+基因型患者。接受联合治疗的老年受试者的GGT水平显著更高,联合治疗和年龄的影响在GSTM1-基因型中更大。
GSTMl-和GSTM1-/GSTT1-基因型可能是VPA治疗患者GGT升高的遗传危险因素。然而,尚无法明确GGT升高是否由VPA诱导的肝毒性引起。