Kassahun K, Farrell K, Abbott F
Faculty of Pharmaceutical Science, University of British Columbia, Vancouver, Canada.
Drug Metab Dispos. 1991 Mar-Apr;19(2):525-35.
The severe hepatotoxicity of valproic acid (VPA) is believed to be mediated through reactive metabolites. The formation of glutathione (GSH) and N-acetylcysteine (NAC) adducts of reactive intermediates derived from VPA and two of its metabolites, 2-propyl-4-pentenoic acid (4-ene-) and 2-propyl-2,4-pentadienoic acid [(E)-2,4-diene VPA], was investigated in the rat. Rats were dosed ip with 100 mg/kg of VPA, 4-ene-, or 2,4-diene-VPA, and methylated bile and urine extracts were analyzed by LC/MS/MS and GC/MS, respectively. The GSH conjugate of (E)-2,4-diene VPA was detected in the bile of rats treated with 4-ene- and (E)-2,4-diene VPA. The NAC conjugate was a major urinary metabolite of rats given (E)-2,4-diene VPA and was a prominent urinary metabolite of those animals given 4-ene VPA. The NAC conjugate was also found to be a metabolite of VPA in patients. Both the GSH and NAC adducts were chemically synthesized and their structures established to be 5-(glutathion-S-yl)3-ene VPA and 5-(N-acetylcystein-S-yl)3-ene VPA by NMR and mass spectrometry. In contrast to the very slow reaction of the free acid of (E)-2,4-diene VPA with GSH, the methyl ester reacted rapidly with GSH to yield the adduct. In vivo it appears the diene forms an intermediate with enhanced electrophilic reactivity to GSH as indicated by the facile reaction of the diene with GSH in vivo [about 40% of the (E)-2,4-diene VPA administered to rats was excreted as the NAC conjugate in 24 hr]. The characterization of the GSH and NAC (in humans and rats) conjugates of (E)-2,4-diene VPA suggests that VPA is metabolized to a chemically reactive intermediate that may contribute to the hepatotoxicity of the drug.
丙戊酸（VPA）的严重肝毒性被认为是由反应性代谢产物介导的。研究了VPA及其两种代谢产物2-丙基-4-戊烯酸（4-烯-VPA）和2-丙基-2,4-戊二烯酸[（E）-2,4-二烯-VPA]衍生的反应性中间体与谷胱甘肽（GSH）和N-乙酰半胱氨酸（NAC）加合物的形成。给大鼠腹腔注射100mg/kg的VPA、4-烯-VPA或2,4-二烯-VPA，分别通过LC/MS/MS和GC/MS分析甲基化胆汁和尿液提取物。在接受4-烯-VPA和（E）-2,4-二烯-VPA治疗的大鼠胆汁中检测到（E）-2,4-二烯-VPA的GSH共轭物。NAC共轭物是给予（E）-2,4-二烯-VPA的大鼠的主要尿液代谢产物，也是给予4-烯-VPA的动物的显著尿液代谢产物。在患者中也发现NAC共轭物是VPA的一种代谢产物。GSH和NAC加合物均通过化学合成，并通过核磁共振和质谱确定其结构分别为5-（谷胱甘肽-S-基）-3-烯-VPA和5-（N-乙酰半胱氨酸-S-基）-3-烯-VPA。与（E）-2,4-二烯-VPA游离酸与GSH的非常缓慢的反应相反，甲酯与GSH迅速反应生成加合物。在体内，二烯似乎形成了一种对GSH具有增强亲电反应性的中间体，这从二烯在体内与GSH的容易反应可以看出[给予大鼠的（E）-2,4-二烯-VPA约40%在24小时内作为NAC共轭物排泄]。（E）-2,4-二烯-VPA的GSH和NAC（在人和大鼠中）共轭物的表征表明VPA被代谢为一种可能导致该药物肝毒性 chemically reactive intermediate。
