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PON1 status and neurologic symptom complexes in Gulf War veterans.

In a case of potential exposure to toxic chemicals, it is often difficult to dissect the genetic, physiological, and environmental factors that contribute to illness. A recently published paper (Haley et al. 1999) raises the possibility of a link between detoxication enzyme genotype/ phenotype and the risk of illness in Gulf War veterans. This work builds on a body of interesting data regarding detoxication enzyme polymorphisms and highlights the need to consider both genotypic and phenotypic information in epidemiological studies. Haley et al. (1997) had previously identified six unique symptom complexes, which they suggested could represent neurologic syndromes or injury sustained in the Gulf War. In the present study (Haley et al. 1999), they examined the relationship of polymorphisms in the paraoxonase gene (PON1) to presentation of neurologic symptom complexes in Gulf War veterans. Paraoxonase (PON1) is a high density lipoprotein (HDL)-associated enzyme that metabolizes oxidized lipids and also hydrolyzes arylesters and a number of toxic organophosphorus (OP) compounds, including insecticides and nerve agents (Aldridge 1953b; Geldmacher-von Mallinckrodt and Diepgen 1988; Davies et al. 1996). Haley et al. (1999) found that veterans homozygous for a specific PON1 allele (PON1Q192) were less likely to have neurologic symptom complexes than those possessing the alternate allele (PON1R192). They also noted that low activity of the plasma PON1Q192 isoform distinguished ill veterans from controls even better than the PON1 genotype. According to Haley et al. (1999), these results support the contention that Gulf War-related neurologic syndromes were caused by exposure to toxic chemical compounds. Do their conclusions seem to be justified based on what is known about the human PON1192 protein polymorphism? Ideally, in an OP exposure scenario, the parameters that would be useful for an epidemiological study are (1) an identification of the compounds to which the individual was exposed, (2) a measure of the level of exposure, (3) a determination of the consequence of the exposure (e.g., toxin-mediated depression of cholinesterase levels), and (4) the status of an individual’s genetic factors that contribute to sensitivity or resistance to the specific compound(s) to which the individual was exposed. Unfortunately, for Gulf War exposures, it is difficult to assess the level of exposure to specific chemicals, and little, if any, information is available on cholinesterase levels before and after exposure. Without the availability of exposure information and cholinesterase inhibition data, the authors have focused on measurable parameters: the status of two detoxifying enzyme systems in individuals with symptom complexes. One of these enzymes, butyrylcholinesterase (BChE), acts as a suicide trap for specific toxic OP compounds; that is, once BChE reacts with an OP molecule, the OP is not available for inhibiting cholinesterase, but the enzyme is inactivated in the process (Aldridge 1953a). The second enzyme, PON1, is capable of catalytically hydrolyzing a number of toxic organophosphates (Aldridge 1953b; Geldmacher-von Mallinckrodt and Diepgen 1988; Davies et al. 1996). PON1 is tightly associated with HDL (“good cholesterol”) particles (Blatter et al. 1993), and its main physiological function appears to be the metabolism of oxidized lipids and prevention of vascular disease (Mackness et al. 1991, 1993; Watson et al. 1995). However, PON1 also hydrolyzes (inactivates) various toxic OP compounds including paraoxon, chlorpyrifos oxon, diazoxon, soman, and sarin (Davies et al. 1996). In human populations, PON1 exhibits a substrate-dependent polymorphism; that is, different substrates (OPs) are hydrolyzed at different rates by different isoforms of PON1. Two genetic polymorphisms known in human populations are the L55M substitution and the Q192R substitution (numbering from the initiator methionine that is the only amino acid removed during secretion of this protein from the liver cells into the serum). Haley et al. (1999) noted that PON1R192 homozygotes or PON1Q/R192 heterozygotes were more likely to have neurologic symptom complexes than were individuals homozygous for PON1Q192. In addition, they measured the serum activity of the enzymes and noted that low activity of the plasma PON1Q192 isoform correlated with illness better than the PON1 genotype or the activity levels of the PON1R192 isoform, total arylesterase, total paraoxonase, or BCHE. Altogether, these results suggest that the PON1Q192 allele had a protective effect against neurologic symptom complexes in Gulf War veterans. Here, we will examine the available evidence as to whether it is reasonable that individuals with a specific PON1 status could be more sensitive to the effects of OP compounds than individuals with a different PON1 status, and why this might be so. Historically, it was known that one enzyme isoform hydrolyzed paraoxon at a high rate and the other at a lower rate (Geldmacher-von Mallinckrodt and 1 E-MAIL clem@u.washington.edu; FAX: (206) 543-0754. Insight/Outlook