INVITRO EFFECTS OF VALPROATE AND VALPROATE METABOLITES ON MITOCHONDRIAL OXIDATIONS - RELEVANCE OF COA SEQUESTRATION TO THE OBSERVED INHIBITIONS

被引：85

作者：

PONCHAUT, S

VANHOOF, F

VEITCH, K

机构：

[1] INT INST CELLULAR & MOLEC PATHOL,B-1200 BRUSSELS,BELGIUM

[2] CATHOLIC UNIV LOUVAIN,PHYSIOL CHEM LAB,B-1200 BRUSSELS,BELGIUM

[3] CATHOLIC UNIV LOUVAIN,HORMONE & METAB RES UNIT,B-1200 BRUSSELS,BELGIUM

来源：

BIOCHEMICAL PHARMACOLOGY | 1992年 / 43卷 / 11期

关键词：

D O I：

10.1016/0006-2952(92)90324-C

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The inhibitory effects of valproate (VPA) and nine of its metabolites on mitochondrial oxidations have been investigated. Valproate, 4-ene-VPE, 2,4-diene-VPA and 2-propylglutaric acid inhibited the rate of oxygen consumption by rat liver mitochondrial fractions with long- and medium-chain fatty acids, glutamate (+/- malate), succinate, alpha-ketoglutarate (+ malate) and pyruvate (+ malate) as substrates. Sequestration of intramitochondrial free CoA by valproate and these three metabolites has been demonstrated and quantified. However, CoA trapping could not account for all the inhibitions observed. 2-ene-VPA and 3-oxo-VPA, metabolites formed during the beta-oxidation of valproate, were not capable of trapping intramitochondrial CoA although they were inhibitors of the beta-oxidation of decanoate, probably by inhibition of the medium-chain acyl-CoA synthetase.

引用

页码：2435 / 2442

页数：8

共 36 条

[31]

RUMBACH L, 1986, MOL PHARMACOL, V30, P270

[32]

SHERRATT H S A, 1976, Biochemical Pharmacology, V25, P743, DOI 10.1016/0006-2952(76)90139-8

[33] A SINGLE THERAPEUTIC DOSE OF VALPROATE AFFECTS LIVER CARBOHYDRATE, FAT, ADENYLATE, AMINO-ACID, COENZYME-A, AND CARNITINE METABOLISM IN INFANT MICE - POSSIBLE CLINICAL-SIGNIFICANCE [J].