Effects of valproate and E-2-en-valproate on functional and morphological parameters of rat liver. III. Influence of fasting.
Valproate (VPA) therapy has been associated with a rare but fatal hepatotoxicity. Several possible biochemical mechanisms responsible for the hepatotoxicity have been proposed, but the matter has not been decided. There is some evidence that VPA-associated hepatotoxicity may represent the consequences of a VPA overload on a limited mitochondrial beta-oxidation capacity, causing abnormalities in metabolic pathways. If this assumption is true, fasting-induced increase of endogenous fatty acids, which compete with VPA for beta-oxidation, should enhance the hepatotoxic potential of VPA. Indeed, involuntary fasting because of anorexia, e.g., in children with febrile infections, has been discussed as one clinical risk pattern preceding VPA-associated hepatic fatalities. In the present experiments, the effects of fasting on functional and morphological parameters of the liver were studied in young male rats chronically treated with VPA. E-2-en-VPA (trans-2-en-VPA), a major active metabolite of the beta-oxidation pathway of VPA, was used for comparison. Both drugs were administered at doses of 250 mg/kg i.p. 3 times daily for 1 week. In control rats, a 40-h fasting period resulted in marked mobilization of liver lipid and glycogen stores, alterations in liver enzyme activities, and hyperammonemia. In rats treated with VPA, fasting reduced beta-oxidation of the drug, but seemed not to increase its hepatotoxic potential. Compared to experiments without fasting, alterations in liver enzymes and ammonia levels induced by VPA were less marked or absent in fasted rats, and histopathological examination of liver sections did not indicate degenerative liver lesions in response to drug treatment. Thus, compared to previous rat studies on VPA without fasting, fasting appeared to attenuate VPA's hepatotoxic potency, possibly as a result of fasting-induced increases in carnitine levels. In rats treated with E-2-en-VPA, no indication of hepatotoxicity was evident, and alterations in functional hepatic parameters were less pronounced than with VPA. The data do not indicate that fasting or poor nutrition are risk factors for VPA-associated hepatic injury.
Löscher
W
W
Department of Pharmacology, Toxicology, and Pharmacy, School of Veterinary Medicine, Hannover, Germany.
Wahnschaffe
U
U
Hönack
D
D
Drews
E
E
Nau
H
H
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D005215:Fasting; D008107:Liver Diseases / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014635:Valproic Acid / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*
D014635:Valproic Acid