Lipid Peroxidation of Microsomal Membranes as the Mechanism of 4-Aminopyrazolopyrimidine-Induced Cell Injury in the Rat Liver.

Abstract

The effect of 4-aminopyrazolo [3, 4-d]pyrimidine (4-APP) on lipid peroxidation in rat liver was characterized. In 4-APP (50mg/kg)-treated rats, the amount of lipid peroxides increased from 150 to 380nmol/g of liver. The action of 4-APP on lipid peroxidation was investigated in an in vitro system containing rat liver microsomal phospholipid liposomes, NADPH, purified microsomal NADPH cytochrome c reductase, and Fe3+-ADP complexes. The addition of 4-APP resulted in the enhancement of lipid peroxidation monitored by O2 consumption and the peroxidative cleavage of unsaturated phospholipids. Superoxide dismutase, the iron chelator desferoxaminemethanesulfonate, and ceruloplasmin inhibited the 4-APP-induced lipid peroxidation. In contrast, catalase and sodium benzoate, which are known to scavenge hydrogen peroxide and hydroxyl radicals, failed to prevent phospholipid peroxidation. These findings strongly suggest that the enzymatic reduction of Fe3+-ADP-4-APP complexes by NADPH cytochrome c reductase significantly promoted lipid peroxidation in microsomal phospholipid membranes, and was probably mediated by an active iron-oxygen complex.