Enzyme-mediated selective toxicity of an organophosphate and a pyrethroid: some examples from a range of animals

Abstract

The toxic action of xenobiotics is usually modulated by the action of enzymes which catalyse their metabolism. Thus it is frequently found that selective toxicity is enzyme-mediated. Species differences in toxicity and their biochemical explanations have been of great value in the confirmation of the importance of these enzymes. To demonstrate that a particular enzyme plays a significant role in vivo in the metabolism and toxicity of a compound it is standard practice to modulate its activity in some way and assess the effect of this on toxic action. Modulation can be achieved by treatment with inducers, e.g. phenobarbital and B-naphthoflavone for the mono-oxygenases, gluthathione transferases, carboxylesterases and glucuronyl transferases. Inhibition is also useful, e.g. metyrapone for the mono-oxygenases, organophosphates for the carboxylesterases and pentachlorophenol for the sulphotransferases. A truly non-invasive modulation, however, may be achieved by varying the test species. Thus species differences can be exploited to further the understanding of the modes of action of toxic compounds. Caution is required, however, because species differences in response are often multi-factorial and metabolism can be a minor component. Another pitfall is that the demonstration of a high rate of enzymatic detoxification in vitro does not always correlate with events in viva Examples drawn from work on two insecticides, the organophosphate chlorfenvinphos and the pyrethroid cypermethrin, serve to illustrate some of these considerations.