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Esterase detoxification of acetylcholinesterase inhibitors by human or rat liver in vitro
Citation:
Moser, Virginia (Ginger) AND S. Padilla. Esterase detoxification of acetylcholinesterase inhibitors by human or rat liver in vitro. Society of Toxicology, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
Understanding individual differences in pesticide detoxification across human liver samples can inform human variability in pesticide sensitivity
Description:
Organophosphate (OP) and N-methylcarbamate pesticides inhibit acetylcholinesterase (AChE), but differences in metabolism and detoxification can influence potency of these pesticides across and within species. Carboxylesterase (CaE) and A-esterase (paraoxonase, PON) are considered factors underlying age-related sensitivity differences. We used an in vitro system to measure detoxification of AChE-inhibiting pesticides mediated via these esterases. Recombinant human AChE was used as a bioassay of inhibitor concentration following incubation with detoxifying tissue: liver plus Ca+2 (to stimulate PONs, measuring activity of both esterases) or EGTA (to inhibit PONs, thereby measuring CaE activity). Inhibitory concentrations of aldicarb, chlorpyrifos oxon, malaoxon, methamidophos, oxamyl, paraoxon, and methyl paraoxon were incubated with liver from adult male rat or one of 20 commercially provided human (11-83 years of age) liver samples. Detoxification was the difference in inhibition produced by the pesticide alone or in combination with liver plus Ca+2 or EGTA. Generally, rat liver produced more detoxification than did the human samples. There were large detoxification differences, which were not correlated with age or sex, across human samples for some pesticides (especially malaoxon, chlorpyrifos oxon) but not for others (e.g., aldicarb, methamidophos). Chlorpyrifos oxon was detoxified only in the presence of Ca+2 in both rat and human livers. Detoxification of paraoxon and methyl paraoxon in rat liver was greater with Ca+2, but humans showed less differentiation between Ca+2 and EGTA conditions. This suggests the importance of PON detoxification for these three OPs in the rat, but mostly only for chlorpyrifos oxon in human samples. Malaoxon was detoxified similarly with Ca+2 or EGTA, and the differences across humans correlated with metabolism of p-nitrophenyl acetate, a substrate for CaEs. This suggests the importance of CaEs in malaoxon detoxification. Understanding these individual differences in detoxification can inform human variability in pesticide sensitivity. This abstract may not necessarily reflect official Agency policy