Acute Cytotoxic Mechanisms and Detoxic Mechanisms of Paraquat Poisoning

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The acute cytotoxicity of paraquat, which is a widely used potent herbicide in agriculture and became recently accepted to be a risk factor of Parkinson's disease, is mediated by reactive oxygen species (ROS) produced by their cyclic oxidation-reduction reaction and causes severe injury to the lungs and other multiorgans in mammals. It was classically misunderstood that NADPH-CYP reductase-CYP in the microsomal phase I drug- metabolizing enzyme systems formed ROS as the in vitro toxic mechanisms. However, we discovered that paraquat was first metabolized in the postmicrosomal cytosomal fractions into paraquat monopyridone, which was subsequently hydroxylated by the NADPH-CYP reductase-CYP, including CYP3A, CYP2B and CYP2C, as detoxification systems.The ROS were formed from the outer surface of the mitochondria in the presence of cytoplasmic NADH and injured the mitochondria. As for the mechanisms, we have found an NADH-quinone oxidoreductase activity located on the outer membrane of mitochondria and propose the participation of voltage dependent anion channel (VDAC).When isolated rat mitochondria were incubated wit coexistence of NADH and paraquat, ROS production was raised and resulted into the structural injury. The intensity was suppressed by benzoquinone, a scavenger of O_2^- and decreased by voltage dependent anion channel (VDAC) inhibitors, such as DIDS and DCCD, and anti-VDAC antibody. The activity was positive at the 500 kDa band by zymography on native-PAGE using NBT reduction. This band contained VDAC protein determined by Western blot at 31 kDa.