Hepatotoxicity in Rat Following Administration of Valproic Acid

Sugimoto, Takeshi; Woo, Man; Nishida, Naoki; Takeuchi, Taishi; Y, Sakane; Kobayashi, Yohnosuke

doi:10.1111/j.1528-1157.1987.tb03640.x

Cited by 43 publications

(31 citation statements)

References 13 publications

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“…In the study of Beghi et al [25] , they reported that carnitine deficiency, which is produced with these antiepileptic drugs, is worth noting and may be a part of a more general biochemical effect of antiepileptic drug therapy on lipid metabolism. However, the significant hypocarnitinemia found in the present study was not detected in the study of Ohtani et al [6] and Sugimoto et al [11] .…”

Section: Discussioncontrasting

confidence: 88%

“…In addition, a significant increase of the mean values of GOT in the sera of phenytoin treated cases (P < 0.001) and GPT in the sera of phenobarbital treated cases (P < 0.05) after, in comparison to that before therapy. This finding is supported by the reports of Aldenhovel [28] and Sugimoto et al [11] . Also, the increase in the mean values of pyruvate in phenobarbital treated cases (P < 0.01) and lactate in carbamazepine treated cases (P < 0.01) after, in relation to that before, therapy is in accordance with the findings of Thurston et al [29] and Sugimoto et al [30] .…”

Section: Discussionsupporting

confidence: 86%

“…Other investigators attributed carnitine deficiency in these patients to the sequestration of free CoA [11,12] , inhibition of β-oxidation enzymes [13] by drug metabolites, and recently to the decreased level of L-glutamate and L-ketoglutarate [16] in liver due to antiepileptic drug intake.…”

Section: Discussionmentioning

confidence: 99%

“…Valproate is found to be toxic to rat liver-mitochondria in both in vitro [10] and in vivo [11] . Valproate can inhibit mitochondrial β-oxidation of long-chain fatty acids by formation of valproyl-Co A that sequesters free Co A [12,13] .…”

Section: Introductionmentioning

confidence: 99%

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Carnitine and Liver Functions Assessment in ChildrenTreated with Anticonvulsant Drugs

Abdel-Ghany¹,

Saleem²,

Ghazaly³

et al. 2000

med

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ABSTRACT. This study was conducted to evaluate the impact of antiepileptic drugs on the liver function and L-carnitine levels in children suffering from epilepsy. Sixty epileptic children aged from 1 to 15 years, together with 20 healthy controls were studied. Among them twenty-five children were treated with phenytoin (group I), 25 were treated with carbamazepine (group II) and 10 patients were treated with phenobarbital (group III). In each of the three groups, serum free carnitine levels were significantly decreased after one month of therapy compared with pretherapy levels (p<0.01, p<0.01, p<0.01 respectively). Meanwhile, the levels of L-carnitine in treated children collectively were significantly decreased in comparison with healthy children (p<0.01). Hypocarnitinemia was detected in 28% of group I, 56% of group II , and 30% of group III. Serum SGOT was significantly increased in patients treated with phenytoin and phenobarbital (p<0.01, p<0.05 respectively) compared with pretherapy levels. Whereas serum lactate and total bilirubin were significantly increased after therapy in patients treated with carbamazepine in comparison to that before significantly increased (p<0.05 for each) in comparison with controls. Moreover, a significant negative correlation was found between values of carnitine and both lactate (p<0.01) and lactate/pyruvate ratio (p<0.05) after therapy in carbamazepine treated group. It should be taken into account that carnitine rich food in the form of milk and milk products must be taken as a supplement to the antiepileptic drugs especially carbamazepine.

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Section: Discussioncontrasting

confidence: 88%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Carnitine and Liver Functions Assessment in ChildrenTreated with Anticonvulsant Drugs

Abdel-Ghany¹,

Saleem²,

Ghazaly³

et al. 2000

med

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“…Experimentally, valproate consistently inhibited @-oxidation and hepatic ketogenesis in vivo (7,8) and in vitro (6,11). In fasted adult rats, the valproate-induced hypoketonemia was not associated with a decreased liver carnitine content or an abnormal hepatic acyl carnitinelfree carnitine concentration ratio (32). In other fasted adult rats receiving valproate, plasma P-hydroxybutyrate levels fell almost 90% despite 2-to 3-fold increases, not decreases, in the hepatic content of total and free carnitine; levels of acyl carnitine were unchanged (8).…”

Section: Discussionmentioning

confidence: 84%

Amelioration of Adverse Effects of Valproic Acid on Ketogenesis and Liver Coenzyme A Metabolism by Cotreatment with Pantothenate and Carnitine in Developing Mice: Possible Clinical Significance

Thurston

Hauhart

1992

Pediatr Res

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ABSTRACT. Very young children with organic brain damage, intractable seizures, and developmental retardation are at particular risk of developing fatal hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mechanism of valproate-associated hepatic failure in these children is unclear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into poorly metabolized valproyl CoA and valproyl CoA metabolites. The other theory proposes that the unsaturated valproate derivative 2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates are toxic and directly cause irreversible inhibition of enzymes of B-oxidation. The present study shows for the first time that in developing mice, when pantothenic acid and carnitine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the /3-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatment with carnitine alone was without effect. Findings support the CoA depletion mechanism of valproate inhibition of Boxidation and other CoA-and acetyl CoA-requiring enzymic reactions and stress the role of carnitine in the regulation of CoA synthesis at the site of action of pantothenate kinase. (Pediatr Res 31: 419-423, 1992) The new anticonvulsant drug, valproic acid (2-n-propylpentanoic acid, 2-n-propylvaleric acid), is particularly effective in the treatment of the types of seizures peculiar to infants and young children: infantile myoclonic spasms, febrile seizures, and petit ma1 (absence) (reviewed in Ref. 1). Yet this is the age group that is most susceptible to the hepatotoxic effects of the drug, particularly if the children have organic brain damage and are also receiving other anticonvulsant drugs (2). In a study of possible mechanisms of this complication, we found that valproate reduced the physiologic ketonemia of suckling mice (3, 4) and fasting epileptic children (5). In the livers of normal developing mice, valproate produced extraordinary decreases in the levels of free CoA, acetyl CoA, and free carnitine (4). Concomitantly, the concentration of medium-chain acyl CoA esters [including valproyl CoA and its metabolites (6)] increased some 6-to 7-fold (4). As in our normal developing mice, valproate also reduced plasma P-hydroxybutyrate levels and liver CoA and acetyl CoA levels in fasted adult rats (7, 8). In isolated adult rat hepatocytes, valproate inhibited oxidation of fatty acids and pyruvate, fatty acid synthesis, gluconeogenesis, ketogenesis, and ureagenesis (6, 7,9-11). In view of the 100 or so synthetic and catabolic enzyme reactions requiring CoA or acetyl CoA as substrates, cofactors, or activators, the above diverse ill effects of valproate on liver metabolism can largely be explained by sequestration of free CoA into nonmetabolized or poorly metabolized valproyl CoA and valpro...

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