In vivo formation of the thiol conjugates of reactive metabolites of 4-ene VPA and its analog 4-pentenoic acid.
The terminal olefin metabolite of valproic acid (VPA), 4-ene VPA, is an analog of the experimental hepatotoxin 4-pentenoic acid and is believed to play a role in the hepatotoxicity of VPA. The formation of glutathione and N-acetylcysteine conjugates of the putative electrophilic metabolites of 4-ene VPA and 4-pentenoic acid was studied in vivo in the rat. Animals were treated intraperitoneally with the sodium salts of VPA, 4-ene VPA, (E)-2,4-diene VPA, 4-pentenoic or (E)-2,4-pentadienoic acids, and methylated bile and urine extracts were analyzed by LC/MS/MS and GC/MS techniques. The alpha,beta-unsaturated reactive metabolite of 4-pentenoic acid, 3-oxo-4-pentenoic acid, was isolated and identified as its thiol conjugates. In contrast, 3-oxo-4-ene VPA or its thiol conjugates could not be demonstrated as metabolites even though synthetic standards were available to facilitate their detection. Isolation of the thiol conjugates of 3-oxo-4-pentenoic acid provides the first direct spectroscopic evidence for the in vivo formation of the metabolite of 4-pentenoic acid considered responsible for the irreversible inhibition of fatty acid metabolism. The biliary and urinary metabolite profiles of 4-ene VPA and 4-pentenoic acid revealed basic differences between the in vivo metabolism of these two unsaturated carboxylic acids.
Kassahun
K
K
Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Abbott
F
F
D000111:Acetylcysteine / Q000378:metabolism*; D000818:Animals; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000378:metabolism
D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; C045022:2-propyl-4-pentenoic acid; D014635:Valproic Acid; C009785:4-pentenoic acid; D005978:Glutathione; D000111:Acetylcysteine