Genetic Polymorphisms and Susceptibility

Organisms can differ in the amounts and activities of their B esterases, and the differences affect susceptibility to organophosphorous compounds. Although acetylcholinesterase shows relatively little variation in structure and activity among individuals of a species, other esterases that interact with organophosphorous insecticides differ widely among individuals in a population. For example, several variants of pseudocholinesterase have been noted in human serum, with distinguishing differences related to capability for interaction with particular molecules (for example, succinylcholine and fluoride). A single clinical case report noted that atypical pseudocholinesterase was found in a soldier who suffered adverse effects when exposed to an acetylcholinesterase inhibitor during the Gulf War (Loewenstein-Lichtenstein et al., 1995). Differences in pseudocholinesterase activities did not, however, differentiate between symptomatic and asymptomatic Gulf War veterans when more subjects were studied (Kurt, 1998).

Differences in the biotransformation of organophosphorous compounds play a role in susceptibility to them in organisms of different ages and species. The young are generally more susceptible to acetylcholinesterase inhibition because they are less likely to convert organophosphorous compounds into nontoxic metabolites. Apart from age, different species have different capabilities for organophosphorous biotransformation; for example, avians can be 10 times as susceptible as mammals.

Genetic polymorphisms of A esterases (arylesterases) might play a role in susceptibility of humans and animals to organophosphorous compounds. Although other A esterases exist, the most studied are the paraoxonases, which metabolize, in addition to paraoxon, chlorpyrifos-oxon and diazoxon, the active metabolites of chlorpyrifos and diazinon, respectively, two organophosphorous insecticides used in the Gulf War. At least three gene products exist for paraoxonase. One of the gene products, paraoxonase-1 (PON1), has at least two isozymes (Q, formerly referred to as A; and R, formerly referred to as B). Those isozymes differ in their ability to metabolize organophosphorous insecticides. Population studies have demonstrated a trimodal distribution of paraoxonase activity, reflecting QQ, RR, and QR individuals. Reported individual differences in Q activities suggest that such differences contribute to the varied responses to environmental organophosphorous compounds in people and animals (Brophy et al., 2001; Cowan et al., 2001; Hernandez et al., 1999; La Du et al., 1999). In a small sample of Gulf War veterans, individuals with the neurologic symptom complexes were more likely to have the R allele (heterozygous QR or homozygous R) than to be homozygous Q for the allele (Haley et al., 1999). Animal studies also demonstrate the role of PON1 in organophosphorous metabolism and the varying activity of the differential isozymes. PON1 knockout mice (mice without PON1) were found to be very sensitive to the toxicity of organophosphorous compounds, and following introduction of the enzyme to the knockout animals, the sensitivity to specific organophosphorous compounds varied with the isoform given to the animal. Animals given the Q isozyme were less sensitive to diazoxon while animals given the R isozyme were less sensitive to chlorpyrifos-oxon and paraoxon. It is important to note, however, that although mouse and human Q isoforms are similar, the catalytic efficiencies of their R isozymes differ (Furlong et al., 2000; Li et al., 2000).



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