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A loss of nigrostriatal dopaminergic neurons is the primary neurodegenerative feature of Parkinson's disease. Paraquat, a known redox cycling herbicide, has recently been shown to kill selectively nigrostriatal dopaminergic cells in the mouse model. The purpose of this study was to test the ability of paraquat and other redox cycling pesticides to damage dopaminergic neurons in primary mesencephalic cultures. Addition of paraquat, diquat, or benzyl viologen to mesencephalic cultures induced morphological changes (e.g., dystrophic neuronal processes) consistent with dopaminergic cell injury. The three pesticides also caused cell death as assessed by a reduction of the number of tyrosine hydroxylase-immunoreactive neurons and a dose-dependent decrease in [(3)H]dopamine uptake. Quite interestingly, diquat and benzyl viologen were significantly more toxic than paraquat, probably reflecting their more pronounced ability to trigger redox cycling reactions. The data support a role of redox cycling as a mechanism of dopaminergic cell degeneration and suggest that the property of redox cycling should be taken into consideration when evaluating putative environmental risk factors for Parkinson's disease.

We determine the relative abilities of three bipyridyls (Paraquat P + +, Benzylviologen B + + and Diquat D + +) to stimulate iron-induced lipid peroxidation in relation to their ability to redox cycle and to reduce iron. The ability to redox cycle increases with the redox potential, in the order: P + + < B + + < D + +. The initial rates of Fe3+ reduction increased from P + + to D + + and B + +. NADPH-dependent microsomal lipid peroxidation was measured in different conditions (1) increasing incubation time, 100 microM bipyridyl, 10 microM FeCl3; (2) increasing concentrations of bipyridyls, 10 microM FeCl3, 10 min incubation time; (3) increasing concentrations of FeCl3, 100 microM bipyridyl, 10 min incubation time. Bipyridyls potentiated the production of malondialdehyde (MDA), particularly with the shortest incubation times and the lowest concentrations of FeCl3, in the order of activity P + + < D + + < B + +. The strong correlation between the initial rate of lipid peroxidation and Fe3+ reduction indicates that the rate of Fe3+ reduction determines the intensity of the potentiation effect of bipyridyls on lipid peroxidation--on the condition that the amount of peroxidizable substrate is not the limiting factor.

This report presents qualitative data of the effects of a free radical generator (benzyl viologen) on rat liver. Rats were administered benzyl viologen (0.825 mg per kg of body weight) or saline solution (controls) intraperitoneally, in single daily dosage for 15 days. For microscopic examination animals were killed after 3 or 15 days of treatment. In the control animals, liver ultrastructure remained normal throughout the experiment. But in rats with benzyl viologen it was possible to observe important morphological alterations essentially in mitochondria, frequently forming ring-like bodies. Endoplasmic reticulum was observed as concentric patterns which cover the mitochondria and, on occasion, the lipid droplets within the cell. Increased number of dense granular lysosomes were observed in the apical cytoplasm mainly close to the bile canaliculus. A large quantity of lipid inclusions and cellular degeneration of the liver of treated rats showed a marked dose-response relationship.

The role of active oxygen species and lipid peroxidation in the toxic effects of diquat, paraquat and other bipyridyl herbicides remains controversial. In vitro studies have shown that these compounds are potent generators of active oxygen species by redox cycling and that they stimulate lipid peroxidation. In vivo studies have failed, however, to show clear evidence of lipid peroxidation resulting from toxic exposures to these compounds. We have directly compared the abilities of three bipyridyl herbicides, diquat (DQ), paraquat (PQ) and benzyl viologen (BV), to generate superoxide anion radical (O2-.) in rat liver microsomes and H2O2 in hepatocytes and correlated this with their relative toxicities to a compromised isolated hepatocyte system. DQ was the most potent generator of O2-. and H2O2, being slightly more potent than BV and much better than PQ. This ability of the bipyridyls to generate active oxygen was positively correlated with the ability to induce toxicity in hepatocytes pretreated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) to inhibit their glutathione reductase activity, i.e. DQ greater than BV greater than PQ. DQ caused a rapid depletion of cellular GSH and a concomitant increase in GSSG in this system. Toxicity, measured as loss of plasma membrane integrity, was pronounced after only 30-60 min of incubation and was accompanied by a significant increase in lipid peroxidation. The onset of lipid peroxidation could not be separated temporally from the expression of toxicity. However, the total inhibition of lipid peroxidation by the antioxidants Trolox C, promethazine and N,N'-diphenyl-p-phenylenediamine only delayed toxicity, indicating that, even though lipid peroxidation may play some role in enhancing bipyridyl herbicide toxicity, it is not essential for the toxicity to manifest itself.