Figure 2.

PON1 in toxicology: implications for neurodegenerative diseases. PON1 evolved from lactonases that have a key role in natural immunity, limiting quorum sensing lactones from bacteria. In evolution it acquired promiscuous esterase activities, hydrolyzing compounds of interest in toxicology. Organophosphate pesticides (1) are metabolized to their respective oxon by phase 1 metabolism in the liver (2,3). These oxons are toxic due to their inhibition of acetylcholinesterase, which is associated with several neurodegenerative disorders (4). PON1 hydrolyzes paraoxon (oxon from parathion, from which the name derives) and oxons from many other organophosphates (5) and detoxifies them. Major polymorphisms in PON1 significantly change this activity (6) and may be associated with increased susceptibility to neurodegenerative disorders as discussed in the text.