Evidence for the catalytic activity of endogenous iron in the lipid peroxidative destruction of heme by allylisopropylacetamide in the rat liver

Abstract

1. 1. The newly defined property of allylisopropylacetamide (AIA) to decrease the hepatocyte concentration of glutathione (GSH) is described. The decrease in glutathione level was time-dependent and reductions of up to 50% in the values were observed during 4–16hr after one injection of AIA. This interval corresponded to the period during which the microsomal conjugated dienes and the lipid peroxidative activity were markedly increased and a sustained depression in the microsomal heme content was observed. 2. 2. When deferoxamine, an iron chelator, was administered to rats in conjunction with AIA, the ability of AIA to increase lipid peroxidative activity of the microsomal membranes was significantly decreased. Moreover, the addition of deferoxamine to an AIA incubation medium markedly reduced the extent of destruction of cytochrome P-450 and heme, and totally inhibited microsomal lipid peroxidative activity. It is suggested that (1) the depletion of the hepatocytes GSH concentration is caused by a biotransformed derivative of AIA, and (2) that the iron released through AIA mediated degradation of cellular heme, in the presence of depleted hepatocyte GSH levels, promotes lipid peroxidation and the destruction of microsomal heme and cytochrome P-450.