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Esterase detoxification of acetylcholinesterase inhibitors using human liver samples in vitro
Citation:
Moser, Ginger AND S. Padilla. Esterase detoxification of acetylcholinesterase inhibitors using human liver samples in vitro. TOXICOLOGY. Elsevier Science Ltd, New York, NY, , 11-20, (2016).
Impact/Purpose:
This in vitro system of measuring detoxification allows assessment of individual differences that 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, PON1) 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 PON1s, measuring activity of both esterases) or EGTA (to inhibit PON1s, thereby measuring CaE activity). AChE inhibitory concentrations of aldicarb, chlorpyrifos oxon, malaoxon, methamidophos, oxamyl, paraoxon, and methylparaoxon were incubated with liver homogenates from adult male rat or one of 20 commercially provided human (11-83 years of age) liver samples. Detoxification was defined as the difference in inhibition produced by the pesticide alone and inhibition measured in combination with liver plus Ca+2 or liver plus EGTA. Generally, rat liver produced more detoxification than did the human samples. There were large detoxification differences across human samples for some pesticides (especially malaoxon, chlorpyrifos oxon) but not for others (e.g., aldicarb, methamidophos); for the most part these differences did not correlate with age or sex. Chlorpyrifos oxon was fully detoxified only in the presence of Ca+2 in both rat and human livers. Detoxification of paraoxon and methylparaoxon in rat liver was greater with Ca+2, but humans showed less differentiation than rats between Ca+2 and EGTA conditions. This suggests the importance of PON1 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.
