Relative inhibitory potencies of chlorpyrifos oxon, chlorpyrifos methyl oxon, and mipafox for acetylcholinesterase versus neuropathy target esterase.
The relative inhibitory potency (RIP) of an organophosphorus (OP) inhibitor against acetylcholinesterase (AChE) versus neuropathy target esterase (NTE) may be defined as the ratio [k(i)(AChE)/k(i)(NTE)], where k(i) is the bimolecular rate constant of inhibition for a given inhibitor against each enzyme. RIPs greater than 1 correlate with the inability of ageable OP inhibitors or their parent compounds to produce OP compound-induced delayed neurotoxicity (OPIDN) at doses below the LD50. The RIP for chlorpyrifos oxon (CPO) is >>1 for enzymes from hen brain homogenate, and the parent compound, chlorpyrifos (CPS), cannot produce OPIDN in hens at sublethal doses. This study was carried out to test the hypothesis that the RIP for the methyl homologue of CPO, chlorpyrifos methyl oxon (CPMO), is >>1 and greater than the RIP for CPO. Mipafox (MIP), an OP compound known to produce OPIDN, was included for comparison. Hen brain microsomes were used as the enzyme source, and k(i) values (mean +/- SE, microM(-1) min(-1)) were determined for AChE and NTE (n = 3 and 4 separate experiments, respectively). The k(i) values for CPO, CPMO, and MIP against AChE were 17.8 +/- 0.3, 10.9 +/- 0.1, and 0.00429 +/- 0.00001, respectively, and for NTE were 0.0993 +/- 0.0049, 0.0582 +/- 0.0013, and 0.00498 +/- 0.00006, respectively. Corresponding RIPs for CPO, CPMO, and MIP were 179 +/- 9, 187 +/- 4, and 0.861 +/- 0.011, respectively. The results demonstrate that RIPs for CPO and CPMO are comparable, markedly different from that for MIP, and >>1, indicating that CPS methyl, like CPS, could not cause OPIDN at sublethal doses.
Kropp
Timothy J
TJ
Toxicology Program, Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor 48109, USA.
Richardson
Rudy J
RJ
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002478:Cells, Cultured; D002645:Chickens; D004390:Chlorpyrifos / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D005260:Female; D007306:Insecticides / Q000633:toxicity*; D007531:Isoflurophate / Q000031:analogs & derivatives* / Q000633:toxicity*; D007700:Kinetics; D007928:Lethal Dose 50; D016014:Linear Models
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D007531:Isoflurophate; C005238:mipafox; D002265:Carboxylic Ester Hydrolases; C021859:neurotoxic esterase; D004390:Chlorpyrifos