Parathion species differences

When methyl parathion was given orally to rats at doses of 1.5 mg/kg and to guinea pigs at 50 mg/kg, plasma, erythrocyte, and brain cholinesterase activity was maximally inhibited within 30 minutes after administration. In rodents of both species that died after acute intoxication, brain cholinesterase levels decreased to 20% of control values and often to 5-7% (Miyamoto et al. 1963b). The species difference in susceptibility to orally administered methyl parathion is noted in Section 3.2.2.1. 

Although my Laboratory has used these principles to study the toxicities caused by large doses of drugs, there is every reason to believe that these principles will be equally applicable in studying species differences in the effects of pesticides. Indeed, it is now believed that compounds such as piperonyl butoxide and parathion inhibit cytochrome P-450 enzymes through the formation of chemically reactive metabolites. The specificity of the effects of these substances presumably occurs either because the chemically reactive metabolites have an unusually high affinity for the cytochrome P-450 enzymes or because they are so shortlived that they never leave the immediate environment of the active sites of the enzymes. The use of other "suicide enzyme inhibitors" offers exciting possibilities. 

The blood enzymes appear to act as buffers for the enzymes in the tissue. There is little inhibition of tissue enzyme until much of the blood enzyme is inhibited. The RBC-ChE appears to be more important than the plasma enzyme in this regard. In two studies,35,36 a small dose of DFP in humans inhibited about 90% of the plasma enzyme activity but only 15% to 20% of RBC-ChE activity. Symptoms correlated with depression of RBC-ChE, but not with depression of BuChE (see the Central Nervous System and Behavior section below). In humans, some pesticides, such as parathion,79 systox,37 and malathion,20 also preferentially inhibit the plasma enzyme, while others, such as dimefox39 and mevinphos,40 initially bind with the RBC enzyme. In animals, there appears to be a species difference, inasmuch as parathion preferentially inhibits RBC-ChE in rats and the plasma enzyme in dogs.20... 

Many differences in overall toxicity between males and females of various species are known (Table 9.1). Although it is not always known whether metabolism is the only or even the most important factor, such differences may be due to gender-related differences in metabolism. Hexobarbital is metabolized faster by male rats thus female rats have longer sleeping times. Parathion is activated to the cholinesterase inhibitor paraoxon more rapidly in female than in male rats, and thus is more toxic to females. Presumably many of the gender-related differences, as with the developmental differences, are related to quantitative or qualitative differences in the isozymes of the xenobiotic-metabolizing enzymes that exist in multiple forms, but this aspect has not been investigated extensively. 

Species variation in the oxidation of xenobiotics, in general, is quantitative (Table 9.4), whereas qualitative differences, such as the apparent total lack of parathion oxidation by lobster hepatopancreas microsomes, are seldom observed. Although the amount of P450 or the activity of NADPH-cytochrome P450 reductase seems to be related to the oxidation of certain substrates, this explanation is not always satisfactory... 

Reductive reactions, like oxidation, are carried out at different rates by enzyme preparations from different species. Microsomes from mammalian liver are 18 times or more higher in azoreductase activity and more than 20 times higher in nitroreductase activity than those from fish liver. Although relatively inactive in nitroreductase, fish can reduce the nitro group of parathion, suggesting multiple forms of reductase enzymes. 

Comparison of the values of E for the various pesticides and the neutral and anionic species of the simple nitrophenol indicates that a much higher activation energy is associated with adsorption of neutral molecules (parathion and the neutral nitrophenol) than with adsorption of anions (2,4-D, DNOSBP, and the anionic nitrophenol). This observation suggests the possibility of two different rate-limiting steps in the intraparticle transport mechanism. Current studies are being directed toward more detailed exploration of the observed thermokinetic phenomena. 

If the activity of the P450 system varies among animal species, we would expect this to be reflected in the degree of activation of a phosphorothioate insecticide such as parathion. As shown in Figure 9.2, this appears to be the case (Whitehouse and Ecobichon, 1975). The approximately 20-fold difference in paraoxon production by the tissue homogenates probably reflects a combination of cytochrome P450 monooxygenase and esterase activities. 

Figure 9.2 Initial rates of parathion desulfuration by hepatic microsomes of representative males and females of different mammalian species. Activity was determined at 37°C using an initial substrate concentration of 2 x 10 1 M parathion. The bars represent the mean activities (nmol of paraoxon/min/mg protein) of the number of animals shown. The lines represent the standard deviations of the mean values. (From Whitehouse, L.W. and Ecobichon, D.J., Pestic. Biochem. Physiol., 5, 314,1975. With permission.)...

Such a pathway does, however, exist in insects. In the latter species, parathion and malathion act as prodrugs. They are metabolized by oxidative desulfurization to give the active anticholinesterases which irreversibly bind to the insects acetylcholinesterase enzymes and lead to death. In mammals, the same compounds are metabolized in a different way to give inactive compounds which are then excreted (Fig. 11.59). 

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