INFLUENCE OF THE XANTHINE DERIVATIVE DENBUFYLLINE AND THE ANTIINFLAMMATORY AGENT NABUMETONE ON MICROSOMAL FREE-RADICAL PRODUCTION AND LIPID-PEROXIDATION IN RAT-LIVER

The influence of denbuylline, nabumetone and its main metabolite BRL 1 0 720 on iron stimulated lipid peroxidation (LPO), cytochrome P 450 de pendent H2O2 and chemiluminescence (CL) production was investigated in rat Liver microsomes in vitro (10(-5)-10(-3) M) and in vivo after tre at ment of rats (5-300 mg/kg b.m. orally on three consecutive days). I n rat Liver slices the release of thiobarbituric acid reactants (TEAR) was measured after I hour of incubation with the drugs. Denbufylline, nabumetone and BRL 10 720 exerted a significant inhibition of iron st imulated LPO in vitro. Nabume- tone showed the strongest antioxidative activity, which was also seen in liver slices. These antioxidative ef fects were not found after in vivo treatment of rats. Denbufylline (10 (-3) M) additionally inhibited H2O2 formation and the luminol and luci genin amplified CL in vitro. Unexpectedly, nabumetone increased H2O2 f ormation both in vitro and in vivo, but in vitro only lucigenin amplif ied CL. BRL 10 720 increased microsomal H2O2 production in vivo. Moreo ver, BRL 10 720 enhanced CL in vitro and in vivo significantly, which is interpreted as an increase of the production of superoxide anion ra dicals and other reactive oxygen ape cies such as H2O2, but lipid pero xidation in Liver microsomes was not enhanced. These results suggest t hat denbufylline, nabumetone and BRL 10 720 in contrast to the in vitr o effects did not exert antioxidative activities after treatment of ra ts. On the contrary, BRL 10 720 was found to support the formation of reactive oxygen species in liver microsomes.