The effect of valproic acid on hepatic and plasma levels of 15-F2t-isoprostane in rats.
The mechanism by which valproic acid (VPA) induces liver injury remains unknown, but it is hypothesized to involve the generation of toxic metabolites and/or reactive oxygen species. This study's objectives were to determine the effect of VPA on plasma and hepatic levels of the F(2)-isoprostane, 15-F(2t)-IsoP, a marker for oxidative stress, and to investigate the influence of cytochrome P450- (P450-) mediated VPA biotransformation on 15-F(2t)-IsoP levels in rats. In rats treated with VPA (500 mg/kg), plasma 15-F(2t)-IsoP was increased 2.5-fold at t(max) = 0.5 h. Phenobarbital pretreatment (80 mg/kg/d for 4 d) in VPA-treated rats increased plasma and liver levels of free 15-F(2t)-IsoP by 5-fold and 3-fold, respectively, when compared to control groups. This was accompanied by an elevation in plasma and liver levels of P450-mediated VPA metabolites. Pretreatment with SKF-525A (80 mg/kg) or 1-aminobenzotriazole (100 mg/kg), which inhibited P450-mediated VPA metabolism, did not attenuate the increased levels of plasma 15-F(2t)-IsoP in VPA-treated groups. Plasma and hepatic levels of 15-F(2t)-IsoP were further elevated after 14 d of VPA treatment compared to single-dose treatment. Our data indicate that VPA increases plasma and hepatic levels of 15-F(2t)-IsoP and this effect can be enhanced by phenobarbital by a mechanism not involving P450-catalyzed VPA biotransformation.
Tong
Vincent
V
Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Chang
Thomas K H
TK
Chen
Jie
J
Abbott
Frank S
FS
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D015237:Dinoprost / Q000031:analogs & derivatives*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D028441:F2-Isoprostanes / Q000097:blood / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D008054:Lipid Peroxides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances; D014230:Triazoles / Q000494:pharmacology; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D028441:F2-Isoprostanes; D008054:Lipid Peroxides; D017392:Thiobarbituric Acid Reactive Substances; D014230:Triazoles; C033020:1-aminobenzotriazole; C075750:8-epi-prostaglandin F2alpha; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D015237:Dinoprost; D010634:Phenobarbital