Influence of Paraquat on Microsomal Oxygen uptake

Abstract

Lipid peroxidation by activated forms of oxygen has been proposed as a mechanism of paraquat (PQ) toxicity by Bus et al. (Environm. Hlth.Perspect. 16, 139, 1976). These authors demonstrated increased peroxidation of microsomal lipids by PQ as measured by formation of malondialdehyde (MDA), whereas other authors found inhibition (Montgomery, Tox.appl.Pharmacol. 36, 543, 1976; Jlett et al., ibid. 28, 216, 1974). In mice liver microsomes the NADPH dependent oxygen uptake is increased by PQ in a dose dependent manner. The observed Km of 3.10−4 M for PQ shows a relatively low affinity of PQ to the sensitive site. In contrast, MDA formation is inhibited with a lower concentration of PQ (Ki: 6.10−5 M) Other inhibitors of MDA formation such as EDTA, catechol, neotetrazolium do not influence the PQ-induced oxygen consumption. Induction by phenobarbitone increases the PQ-induced oxygen consumption but not the formation of MDA, suggesting a role for NADPH-cytochrome c-reductase as does also the insensitivity to CO. In the presence of PQ 2 moles of NADPH were oxidized per mole oxygen, while in its absence the ratio was close to 1. Oxidation of methanol to formaldehyde was enhanced by PQ. The above PQ effects are similar to those of menadione, which is a substrate of NADPH-cytochrome c-reductase (Nishibayashi et al., Biochem.Biophys.Acta 67, 520, 1963) and is effective in much lower concentrations with a NADPH/oxygen ratio of 1. These results are consistent with an increased formation of hydrogen peroxide by PQ and the subsequent cleavage to oxygen and water by catalase. Under our experimental conditions a divergence between MDA formation and oxygen consumption — both are considered as parameters of lipid peroxidation — becomes obvious.