MECHANISM OF PARAQUAT ACTION ON MICROSOMAL OXYGEN REDUCTION AND ITS RELATION TO LIPID PEROXIDATION

Liver microsomes from control and phenobarbital-induced (PB) mice have been used to study the effect of paraquat (PQ) on oxygen reduction and malondialdehyde (MDA) formation. PQ increased the rate of NADPH-dependent oxygen uptake considerably in control and even more in PB-induced microsomes, but reduced the total amount of oxygen consumed, thus increasing the NAPDH O2 ratio from about unity to 2. This effect is not specific to PQ since menadione, electron acceptor for NADPH-cytochrome c-reductase, can produce the same phenomenon. Hydrogen peroxide was only a minor product in the unstimulated reaction, but accounted for all the oxygen consumed in the reaction stimulated by PQ. This was shown by methanol oxidation and after inhibition of catalase by sodium azide in vitro and by 2-amino-1,2,4-triazole (AT) in vivo. In contrast to previously published results lipid peroxidation as measured by MDA formation was not increased but rather inhibited by concentrations of PQ (Ki 0.064 mm) lower than those needed to stimulate oxygen uptake (Km 0.60 mm) and to inhibit p-nitroanisole-O-demethylation (Ki 0.58 mm). The 10-fold concentration difference suggests different mechanisms for the action of PQ in these processes. This observation does not favor the concept of lipid peroxidation as the mechanism of PQ toxicity. © 1979.