Species Differences in Paraoxonase Mediated Hydrolysis of Several Organophosphorus Insecticide Metabolites

Abstract

Paraoxonase (PON1) is a calcium dependent enzyme that is capable of hydrolyzing organophosphate anticholinesterases. PON1 activity is present in most mammals and previous research established that PON1 activity differs depending on the species. These studies mainly used the organophosphate substrate paraoxon, the active metabolite of the insecticide parathion. Using serum PON1 from different mammalian species, we compared the hydrolysis of paraoxon with the hydrolysis of the active metabolites (oxons) of two additional organophosphorus insecticides, methyl parathion and chlorpyrifos. Paraoxon hydrolysis was greater than that of methyl paraoxon, but the level of activity between species displayed a similar pattern. Regardless of the species tested, the hydrolysis of chlorpyrifos-oxon was significantly greater than that of paraoxon or methyl paraoxon. These data indicate that chlorpyrifos-oxon is a better substrate for PON1 regardless of the species. The pattern of species differences in PON1 activity varied with the change in substrate to chlorpyrifos-oxon from paraoxon or methyl paraoxon. For example, the sex difference observed here and reported elsewhere in the literature for rat PON1 hydrolysis of paraoxon was not present when chlorpyrifos-oxon was the substrate.

Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict In Vivo Red Blood Cell Acetylcholinesterase Inhibition Following Exposure to Chlorpyrifos in the Caucasian and Chinese Population

“…Preliminary experiments were conducted to define the optimal incubation conditions that are linear in time and with the liver microsomal concentration (data not shown). The kinetic incubations were carried out in 50 mM Tris–HCl (pH 7.4) containing 2 mM CaCl 2 (to stimulate the PON1 activity) (Carr et al , 2015), and CPO (at a final concentration range of 25–1500 µM, added from 100 times concentrated stock solutions in DMSO). After 1 min preincubation, the reaction was initiated by adding either 5 µl of Caucasian (final concentration 0.5 mg/ml) or 2.5 µl of Chinese liver microsomes (final concentration 0.25 mg/ml) and incubated for 5 min in a 37°C water bath.…”

A review of paraoxonase 1 properties and diagnostic applications

“…PON1 hydrolysis oxon metabolites in most mammals (Carr et al 2015). Experiments with PON1 knockout mice showed a dramatic sensitivity increase to diazoxon exposure, which resulted in 80% inhibition of cholinoesterase in comparison to wild type mice.…”

“…chlorpyrifos oxon and diazoxon, than its esterolytic abilities towards diazinon and paraoxon (Li et al 2000). Its activity also differs between species, PON1 activity is higher in rabbits and rats than in cows, pig and horses (Carr et al 2015). Another group of synthetic substrates are aromatic esters.…”

Toward Understanding the Catalytic Mechanism of Human Paraoxonase 1: Site-Specific Mutagenesis at Position 192

“…Overall, our results suggest that, due to the presence of different amino acid residues at position 192, h-PON1 can hydrolyse different substrates at different rates. In fact, a difference in the OP-hydrolyzing activity of PON1 from different species was observed recently [ 46 ]. At this juncture, we speculate that in different organisms, PON1 can participate in the metabolism of different substrates depending on the need of the organism.…”