Valproic acid glucuronidation is associated with increases in 15-F2t-isoprostane in rats

Oxidative stress has been associated with valproic acid (VPA) treatment in rats and studies are ongoing to examine the relationship between VPA biotransformation and the increase in the lipid peroxidation biomarker 15-F2t-isoprostane (15-F2t-IsoP). This study investigated the effects of modulating VPA-1-O-acyl glucuronide (VPA-G) formation on 15-F2t-IsoP levels. Adult male Sprague-Dawley rats were pretreated with phenobarbital (PB; 80 mg/kg/day for 4 days), (-)-borneol (320 mg/kg), or a combination of both before VPA treatment (500 mg/kg). Liver VPA-G levels were determined by LC/MS and plasma and liver 15-F2t-IsoP levels were measured using an EIA method. PB, an inducer of VPA glucuronidation, elevated both liver VPA-G and plasma and liver 15-F2t-IsoP levels in VPA-treated rats. (-)-Borneol, an inhibitor of glucuronidation, significantly reduced the levels of liver VPA-G and decreased plasma and liver 15-F2t-IsoP levels in both the VPA and the PB + VPA groups. (-)-Borneol and PB alone did not elevate 15-F2t-IsoP levels compared to the vehicle control groups. The fluorinated analogue of VPA, alpha-fluoro-VPA, was a poor substrate for glucuronidation and did not elevate 15-F2t-IsoP levels. In summary, the VPA-induced formation of 15-F2t-IsoP is apparently associated with VPA glucuronidation.