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Gulf War and Health: Volume 1. Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines
blocking drug succinylcholine, which relies heavily on BuChE for its hydrolysis, exhibit unexpectedly prolonged paralysis of the respiratory muscles (succinylcholine apnea) because they possess an atypical BuChE. Individuals with atypical BuChE (i.e., aspartate rather than glycine at position 70) (McGuire et al., 1989) are incapable of metabolizing succinylcholine and are also less sensitive to some inhibitors (Neville et al., 1992). Atypical variants of BuChE are encountered in less than 5 percent of the general population, although this may vary in specific subpopulations (Ehrlich et al., 1994).
The possibility has been raised that individuals with atypical BuChE may be more susceptibile to PB toxicity (Loewenstein-Lichtenstein et al., 1995). This suggestion was based on observations of a single patient, homozygous for atypical BuChE, who manifested severe symptoms of toxicity during and immediately following the administration of PB. Since the serum BuChE in this individual was much less susceptible to inhibition by PB (and other carbamate ChE inhibitors), it was suggested that the decreased “buffering capacity” of atypical BuChE would lead to an abnormal accumulation of PB and signs of toxicity.
Hypothetically, the inhibition of plasma esterases by agents such as PB could also represent a loss of capacity to “scavenge” (hydrolyze) other xenobiotics that are esters, leading to their accumulation and toxic consequences (Loewenstein-Lichtenstein et al., 1995; Abou-Donia et al., 1996a,b; Shen, 1998). The possible importance of a scavenger role for BuChE in PB toxicity is suggested by the observation that Wistar rats, which constitutionally have lower levels of BuChE than the Sprague-Dawley strain, also exhibit more exaggerated acoustic startle responses following exposure to PB (Servatius et al., 1998). However, Lotti and Moretto (1995) question the importance of a scavenger role for BuChE as a major contributor to toxicity, noting that even the doses of PB employed in the treatment of myasthenic patients produce little inhibition of BuChE, and further argue that it would be unlikely to play a role in illnesses in Gulf War veterans. Examination of PB-exposed individuals who served in the Gulf War and reportedly are suffering from neurological problems failed to detect any differences between their BuChE activities and those of controls (Haley and Kurt, 1997).
Paraoxonase/Arylesterase 1 (PON1)
Polymorphisms are also known to occur in the PON1 gene. Three genotypes (Q, QR, and R) influence the catalytic activity of two alloenzymes, which—acting as paraoxonases/arylesterases—are capable of hydrolyzing organophosphates at different rates and with differing substrate specificities (Adkins et al., 1993; Humbert et al., 1993; Davies et al., 1996). PON1 activity is known to show considerable variation in humans (Mutch et al., 1992). Haley and colleagues (1999) have recently suggested a relationship between polymorphisms and neurological impairment in Gulf War veterans. The authors identified a study population of veterans with symptom complexes (Haley et al., 1997a,b) and characterized the alleles for both PON1 and BuChE in these individuals (Haley and Kurt, 1997). Among ill veterans, there was a greater tendency to