CYTOCHROME-P-450 - CATALYZED FORMATION OF DELTA-4-VPA, A TOXIC METABOLITE OF VALPROIC ACID
CYTOCHROME-P-450 - CATALYZED FORMATION OF DELTA-4-VPA, A TOXIC METABOLITE OF VALPROIC ACID
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DOI：
10.1126/science.3101178
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发表时间：
1987-02-20
期刊：
影响因子：
56.9
通讯作者：
BAILLIE, TA
中科院分区：
文献类型：
--
作者：
RETTIE, AE;RETTENMEIER, AW;BAILLIE, TA
抗癫痫药物丙戊酸（VPA）引起的肝损害被认为是由该药物的不饱和代谢物delta .4-VPA介导的。在对这种肝毒性化合物的生物学来源的研究中，发现来自苯巴比妥处理的大鼠的肝微粒体催化VPA去饱和为。delta .4-VPA。间接证据表明细胞色素P-450是起作用的酶，这一结论得到了纯化和重组形式的血红蛋白的研究的证实，该血红蛋白催化VPA氧化为4-和5-羟基丙戊酸以及。delta .4-VPA。非活化烷基取代基的去饱和代表了细胞色素P-450的一种新的代谢功能，可能是通过将底物转化为瞬时自由基中间体进行的，该中间体在重组（醇形成）和消除（烯烃产生）途径之间划分。这些发现对烯烃的代谢产生具有广泛的意义，并可能解释当VPA与强效酶诱导抗惊厥药（如苯巴比妥）联合使用时，其肝毒性潜在增加。
Liver damage induced by the antiepileptic drug valproic acid (VPA) is believed to be mediated by an unsaturated metabolite of the drug, .DELTA.4-VPA. In studies of the biological origin of this hepatotoxic compound, it was found that liver microsomes from phenobarbital-treated rats catalyzed the desaturation of VPA to .DELTA.4-VPA. Indirect evidence suggested that cytochrome P-450 was the responsible enzyme, a conclusion that was verified by studies with a purified and reconstituted form of the hemoprotein, which catalyzed the oxidation of VPA to 4- and 5-hydroxyvalproic acid and to .DELTA.4-VPA. Desaturation of a nonactivated alkyl substituent represents a novel metabolic function of cytochrome P-450 and probably proceeds via the conversion of substrate to a transient free radical intermediate, which partitions between recombination (alcohol formation) and elimination (olefin production) pathways. These findings have broad implications with respect to the metabolic generation of olefins and may explain the increased hepatotoxic potential of VPA when it is administered in combination with potent enzyme-inducing anticonvulsants such as phenobarbital.