Paraoxonase polymorphisms and toxicity of organophosphates

In 1946, it was found that certain organophophorus (OP) insecticides could be enzymatically hydrolyzed by plasma (Mazur, 1946). Seminal studies by Aldridge (1953) indicated that A-esterases were capable of hydrolyzing OPs, whereas B-esterases [such as acetylcholinesterase (AChE)] reacted with a single OP molecule and were thus inhibited by this “suicide reaction”. Aldridge's proposal that an A-esterase hydrolyzed both phenylacetate and paraoxon was conclusively proven several decades later, when it was shown that recombinant paraoxonase/arylesterase catalyzed both activities (Gan et al., 1991). Studies in the late 1970s and early 1980s indicated that the plasma hydrolytic activity toward paraoxon was polymorphically distributed in human populations (Playfer, 1976; Eckerson et al., 1993; Mueller et al., 1983), suggesting a genetically based differential susceptibility to OP toxicity.