Like iron ions copper ions are also able to stimulate the NADPH-dependent lipid peroxidation in rat liver microsomes. This effect is strongly dependent on the concentration of Cu2+ added. Initial concentrations of Cu2+ above 50 microM completely inhibit the formation of malonaldehyde. The activator and inhibitor functions may be interpreted by a simultaneous participation of Cu+ ions formed in the chain branching and termination reaction of the free radical lipid peroxidation process. Inhibition studies with pCMB and the His-reagent diethyl pyrocarbonate indicate an essential role of cysteine and histidine residues in the Cu+-NADPH-dependent lipid peroxidation process.