Influence of Bipyridylium Compounds on Microsomal Mixed-Function Oxidation Activities

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Abstract
The two principal bipyridyl herbicides, paraquat and diquat, were investigated for their influence on microsomal mixed‐function oxidation (MFO) activities and on NADPH oxidation rates in lung, liver, and kidney preparations. In lung microsomal preparations, benzphetamine N‐demethylation was found to be inhibited by paraquat and diquat in a concentration‐dependent manner, but ethylmorphine N‐demethylation was unaffected by these bipyridyls. In liver microsomal fractions, both benzphetamine and ethylmorphine N‐demethylases were inhibited by paraquat and diquat. Neither bipyridyl affected MFO activity in kidney preparations. A kinetic investigation of the enzyme inhibition showed that only Vmax was affected by paraquat and diquat, providing the first evidence for noncompetitive inhibition by the bipyridyls. In all microsomal preparations, NADPH oxidation was stimulated significantly by paraquat and to an even greater extent by diquat in the absence or presence of benzphetamine or ethylmorphine. The influence of MFO substrates on the stimulation varied widely among the three organ systems. In lung, paraquat‐ or diquat‐mediated stimulation of NADPH oxidation was equal in the absence of MFO substrates and in the presence of ethylmorphine, but the stimulation was increased in the presence of benzphetamine. Stimulation of NADPH oxidation by the bipyridyls, in liver as well as in kidney preparations, was equal in all situations in the absence of MFO substrates and in the presence of benzphetamine or ethylmorphine, although the quantity of this stimulation was greater in liver than in kidney fractions. It is apparent that the bipyridyls are potent stimulators of in vitro NADPH oxidation in microsomal preparations from several organs. The quantity of the NADPH oxidation stimulation seems to be a decisive factor in the inhibition of xenobiotic metabolism. Whether the stimulation of NADPH oxidation and the noncompetitive inhibition of xenobiotic metabolism play a significant role in bipyridyl toxicity are under further investigation.