Influence of the xanthine derivative denbufylline and the anti-inflammatory agent nabumetone on microsomal free radical production and lipid peroxidation in rat liver

Abstract

The influence of denbufylline, nabumetone and its main metabolite BRL 10,720 on iron stimulated lipid peroxidation (LPO), cytochrome P 450 dependent H2O2 and chemiluminescence (CL) production was investigated in rat liver microsomes in vitro (10(-5)-10(-3) M) and in vivo after treatment of rats (5-300 mg/kg b.m. orally on three consecutive days). In rat liver slices the release of thiobarbituric acid reactants (TBAR) was measured after 1 hour of incubation with the drugs. Denbufylline, nabumetone and BRL 10,720 exerted a significant inhibition of iron stimulated LPO in vitro. Nabumetone showed the strongest antioxidative activity, which was also seen in liver slices. These antioxidative effects were not found after in vivo treatment of rats. Denbufylline (10(-3) M) additionally inhibited H2O2 formation and the luminol and lucigenin amplified CL in vitro. Unexpectedly, nabumetone increased H2O2 formation both in vitro and in vivo, but in vitro only lucigenin amplified CL. BRL 10,720 increased microsomal H2O2 production in vivo. Moreover, BRL 10,720 enhanced CL in vitro and in vivo significantly, which is interpreted as an increase of the production of superoxide anion radicals and other reactive oxygen species such as H2O2, but lipid peroxidation in liver microsomes was not enhanced. These results suggest that denbufylline, nabumetone and BRL 10,720 in contrast to the in vitro effects did not exert antioxidative activities after treatment of rats. On the contrary, BRL 10,720 was found to support the formation of reactive oxygen species in liver microsomes.