Eadie M J, McKinnon G E, Dunstan P R, MacLaughlin D, Dickinson R G
Department of Medicine, University of Queensland, Royal Brisbane Hospital, Australia.
Q J Med. 1990 Dec;77(284):1229-40. doi: 10.1093/qjmed/77.3.1229.
Plasma concentrations of valproate and certain of its metabolites and their patterns of excretion in urine are described in three adults who developed hepatotoxicity during treatment of epilepsy with sodium valproate. One patient also developed a degree of reversible renal insufficiency, whilst another may have had associated infectious mononucleosis. All three cases showed evidence of impaired mitochondrial beta-oxidation of valproate. In one the impairment was at the stage catalysed by fatty acyl-CoA dehydrogenase, in another at the stage catalysed by 3-hydroxyacyl-CoA dehydrogenase and in the third at the stage catalysed by enoyl-CoA hydratase and possibly also at the next stage catalysed by 3-hydroxyacyl-CoA dehydrogenase. The impaired beta-oxidation meant that valproate metabolism was diverted into various alternative pathways. Plasma concentrations of the suspected hepatotoxic metabolite 4-en-valproate were normal for the valproate-treated population in all cases. By analogy with certain spontaneous and acquired human disorders of branched chain amino acid metabolism, it is suggested that valproate-associated hepatotoxicity may represent the consequences of a valproate overload on a limited mitochondrial beta-oxidation capacity, causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.
本文描述了三名在使用丙戊酸钠治疗癫痫期间发生肝毒性的成年人的丙戊酸及其某些代谢产物的血浆浓度，以及它们在尿液中的排泄模式。一名患者还出现了一定程度的可逆性肾功能不全，而另一名患者可能患有传染性单核细胞增多症。所有三例均显示丙戊酸线粒体β氧化受损的证据。其中一例损伤发生在脂肪酰辅酶A脱氢酶催化的阶段，另一例发生在3-羟酰基辅酶A脱氢酶催化的阶段，第三例发生在烯酰辅酶A水合酶催化的阶段，可能还发生在下一个由3-羟酰基辅酶A脱氢酶催化的阶段。β氧化受损意味着丙戊酸代谢转向各种替代途径。在所有病例中，疑似肝毒性代谢产物4-烯丙戊酸的血浆浓度对于接受丙戊酸治疗的人群来说是正常的。通过与某些自发的和后天获得的人类支链氨基酸代谢紊乱进行类比，有人提出丙戊酸相关的肝毒性可能代表丙戊酸负荷超过有限的线粒体β氧化能力所导致的后果，从而导致内源性支链氨基酸代谢的有毒产物积累。
