Paraoxon species differences

There are marked species differences in A-esterase activity. Birds have very low, often undetectable, levels of activity in plasma toward paraoxon, diazoxon, pirimi-phos-methyl oxon, and chlorpyrifos oxon (Brealey et al. 1980, Mackness et al. 1987, Walker et al. 1991 Figure 2.10). Mammals have much higher plasma A-esterase activities to all of these substrates. The toxicological implications of this are discussed in Chapter 10. Some species of insects have no measurable A-esterase activity, even in strains that have resistance to OPs (Mackness et al. 1982, Walker 1994). These include the peach potato aphid (Myzus persicae Devonshire 1991) and the... 

Costa, L.G., Richter, R.J., Murphy, S.D., Omenn, G.S., Moml-sky, A.G., Furlong, C.E. (1987). Species differences in serum paraoxonase correlate with sensitivity to paraoxon toxicity. In Toxicology of Pesticides Experimental Clinical and Regulatory Perspectives (L.G. Costa, C.L. Galli, S.D. Murphy, eds), pp. 263-6. Springer-Verlag, Heidelberg. 

Chatthopadhay DP, Dighe SK, Nashikkar AB et al. (1986). Species differences in the in vitro inhibition of grain acetylcholinesterase and carboxyl esterase by mipafox, paraoxon and soman. Pest Biochem Physiol, 26, 202-208. 

Some species differences are due to differences in the response of the organism to insult or in the repair mechanisms available. There may be very simple differences for example, rats are susceptible to certain rodenticides which they ingest by mouth, as unlike most other mammals, they are unable to vomit. There may be differences in receptor sensitivity such as for the organophosphorus compound paraoxon (see figure 4,25). Thus... 

The apparent IC50 for test compounds differs between the cell lines, possibly reflecting species differences. However, ratios of ICjo values for NTE AChE show similar patterns >40 for m>n-OPIDN-inducing compounds (paraoxon and malaoxon) and those unlikely to cause OPfDN (chlorpyrifos-oxon, dichlorvos. and trichlorphon) low ratios (some <1) for the other compounds, all of which induce OPIDN. IC50 values for inhibition of esterases are lower than those for cytotoxicity. 

Evidence that PONl plays a role in modulating the in vivo toxicity of OPs has emerged over the past 20 years, although it had already been noted that species differences in PONl activity correlated with suscepHbility to OP toxicity (Costa et al., 1987 Furlong et al., 2000). A previous study by Main (1956) showed that intravenous administration of partially purified PONl from rabbit serum would protect rats from the toxicity of paraoxon therefore, several initial studies followed a similar approach. Administration (by the intravenous route) of purified rabbit PONl to rats protected the animals from acetylcholinesterase (AChE) inhibition by chlorpyrifos oxon and paraoxon (Costa et al., 1990). Further studies in mice provided evidence that intravenous administration... 

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. 

Carboxylamidase activity toward p-nitroacetanilide has been detected in different insect species from the orders Lepidoptera, Orthoptera, and Dictyoptera. The carboxylamidase from fall army worm larvae has been purified. The purified enzyme is a monomer with a molecular weight of 59,000-60,000 Da. The enzyme is inhibited by the hydrolase inhibitors paraoxon, triphenyl phosphate, eserine, and phenylmethylsulfonyl fluoride, showing I50 values of 4.7 iM, 0.2 mM, 16 iM, and 90 iM, respectively. Activity is also completely inhibited by the organophosphorus insecticides profenfos and dichlorvos at 0.1 mM. The enzyme is active toward other amides, such as acetanilide and phenacetin, and various a- and p-naphtholic esters. Based on the purification factor, substrate specificity, and sensitivity to hydrolase inhibitors, the carboxylamidase appears to be different from carboxy-lesterases in the fall army worm (Yu and Nguyen, 1998). 

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.)...

Johnson, J., and Wallace, K. (1987). Species-related differences in the inhibition of brain acetylcholinesterase by paraoxon and tnalaoxon, Toxicol Appl Pharmacol 88,234-241. 

The rank order for these compounds is similar but not identical to those previously reported in the literature. For example, chlorpyrifos-oxon has been reported to be a more potent inhibitor of cholinesterase than paraoxon (18,19) and methomyl has been reported to be a more potent inhibitor than aldicarb (id). A number of factors may account for differences that we observe. The magnitude of difference between paraoxon and chlorpyrifos-oxon IC50 values has been shown to be dependent on both the species and tissue from which the cholinesterase is obtained. In addition, assay factors such as contact time (for the enzyme and inhibitor) as well as the removal of excess inhibitor prior to the addition of substrate are critical factors which differ among reported studies. Nevertheless, taken in context of the screening application we propose for this assay, differences in the rank order for various insecticides between our assay and various reports would likely not be a critical issue. 

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