Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates.
The metabolism of 2-n-propyl-4-pentenoic acid (delta 4-VPA), a putative toxic biotransformation product of valproic acid (VPA), was examined in the isolated perfused rat liver. Metabolites excreted into perfusion medium and bile were characterized by GLC and GC/MS techniques and their identities were verified by synthesis. A total of eight metabolites was detected, the structures of which could be best accounted for by initial oxidation reactions catalyzed by either cytochrome P-450 or the fatty acid beta-oxidation complex. Evidence was obtained which indicates that metabolism of delta 4-VPA by each of these enzyme systems can lead to the generation of chemically reactive intermediates which may contribute to the hepatotoxic properties of VPA.
Rettenmeier
A W
AW
Prickett
K S
KS
Gordon
W P
WP
Bjorge
S M
SM
Chang
S L
SL
Levy
R H
RH
Baillie
T A
TA
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D002849:Chromatography, Gas; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D014635:Valproic Acid / Q000378:metabolism* / Q000652:urine
D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; C045022:2-propyl-4-pentenoic acid; D014635:Valproic Acid