VALPROATE-ASSOCIATED HEPATOTOXICITY AND ITS BIOCHEMICAL-MECHANISMS
VALPROATE-ASSOCIATED HEPATOTOXICITY AND ITS BIOCHEMICAL-MECHANISMS
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DOI：
10.1007/bf03259935
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发表时间：
1988-03-01
期刊：
影响因子：
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通讯作者：
DICKINSON, RG
中科院分区：
文献类型：
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作者：
EADIE, MJ;HOOPER, WD;DICKINSON, RG
抗惊厥药物丙戊酸或其钠盐的摄入与偶尔发生的严重、有时是致命的肝毒性有关。全世界可能至少发生了80起病例。该综合征可能影响1/10，000服用药物的人，通常在治疗的最初几周或几个月内发展。大多数病例涉及儿童，通常是接受1种以上抗惊厥药的儿童。多个病例发生在2个家庭。典型的表现是癫痫恶化，意识抑郁加重，以及肝衰竭的临床和生化证据进展。肝脏有时表现为肝细胞坏死，有时表现为广泛的微泡性脂肪变性，同时也发生胆汁淤积性变化。在肝毒性期间，在血液和尿液中发现丙戊酸盐的不饱和代谢产物（特别是4-烯丙戊酸盐）的量增加。在4例病例中，有证据表明丙戊酸盐的β-氧化受损，在1例病例中，结合物分子内重排导致丙戊酸盐葡糖苷酸异构体蓄积。4-烯-丙戊酸盐和2种已知肝毒素（4-烯-戊酸盐和亚甲基环丙乙酸，后者是导致低血糖中毒的原因）之间存在分子结构相似性。丙戊酸盐肝毒性与低甘氨酸中毒和某些自发性异亮氨酸代谢紊乱（丙戊酸盐代谢途径之一类似于异亮氨酸的氧化降解）之间也存在临床和组织病理学相似性。丙戊酸盐的不饱和代谢产物，特别是4-烯-丙戊酸盐，可能导致药物的肝毒性。然而，由于肝毒性似乎涉及特异质因素，在某些情况下，主要缺陷可能是药物β-氧化的遗传性或获得性缺陷。该缺陷可能使丙戊酸盐代谢转向ω-氧化，导致毒素4-烯-丙戊酸盐的形成增加，但也可能导致异亮氨酸衍生的毒性代谢产物的形成增加，因为异亮氨酸衍生物的β-氧化也会受损。
Intake of the anticonvulsant drug valproic acid, or its sodium salt, has been associated with occasional instances of severe and sometimes fatal hepatotoxicity. Probably at least 80 cases have occurred worldwide. The syndrome affects perhaps 1 in 10,000 persons taking the drug, and usually develops in the early weeks or months of therapy. Most instances have involved children, usually those receiving more than 1 anticonvulsant. Multiple cases have occurred in 2 families. The typical presentation is of worsening epilepsy, increasing depression of consciousness, and progressive clinical and biochemical evidence of liver failure. The liver has sometimes shown hepatocyte necrosis, and on other occasions widespread microvesicular steatosis, while cholestatic changes have also occurred. The appearances are interpreted as consistent with a drug toxicity reaction.During the hepatotoxicity increased amounts of unsaturated metabolites of valproate, notably 4-en-valproate, have been found in blood and urine. In 4 cases there has been evidence of impaired β-oxidation of valproate with, in 1 case, accumulation of isomers of valproate glucuronide caused by intramolecular rearrangement of the conjugate. There are molecular structural similarities between 4-en-valproate and 2 known hepatotoxins (4-en-pentanoate and methylenecyclopropylacetic acid, the latter being responsible for hypoglycin poisoning). There are also clinical and histopathological similarities between valproate hepatotoxicity and both hypoglycin poisoning and certain spontaneous disorders of isoleucine metabolism (one pathway ofvalproate metabolism is analogous to oxidative degradation of isoleucine). Unsaturated metabolites of valproate, in particular 4-en-valproate, may contribute to the hepatotoxicity of the drug. However, since the hepatotoxicity appears to involve an element of idiosyncrasy, the primary defect in some cases may be an inherited or acquired deficiency in the drug’s β-oxidation. This defect may divert valproate metabolism towards ω-oxidation, with increased formation of the toxin 4-en-valproate, but may also allow increased formation of a toxic metabolite derived from isoleucine, since β-oxidation of isoleucine derivatives will also be impaired.