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Science 20 February 1987:
Vol. 235. no. 4791, pp. 890 - 893
DOI: 10.1126/science.3101178
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Articles

Science, Vol 235, Issue 4791, 890-893
Copyright © 1987 by American Association for the Advancement of Science

articles

Cytochrome P-450--catalyzed formation of delta 4-VPA, a toxic metabolite of valproic acid

AE Rettie, AW Rettenmeier, WN Howald, and TA Baillie

Liver damage induced by the antiepileptic drug valproic acid (VPA) is believed to be mediated by an unsaturated metabolite of the drug, delta 4-VPA. In studies of the biological origin of this hepatotoxic compound, it was found that liver microsomes from phenobarbital-treated rats catalyzed the desaturation of VPA to delta 4-VPA. Indirect evidence suggested that cytochrome P-450 was the responsible enzyme, a conclusion that was verified by studies with a purified and reconstituted form of the hemoprotein, which catalyzed the oxidation of VPA to 4- and 5-hydroxyvalproic acid and to delta 4-VPA. Desaturation of a nonactivated alkyl substituent represents a novel metabolic function of cytochrome P-450 and probably proceeds via the conversion of substrate to a transient free radical intermediate, which partitions between recombination (alcohol formation) and elimination (olefin production) pathways. These findings have broad implications with respect to the metabolic generation of olefins and may explain the increased hepatotoxic potential of VPA when it is administered in combination with potent enzyme-inducing anticonvulsants such as phenobarbital.


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