RELATIVE POTENCIES OF THE 4 STEREOISOMERS OF ISOMALATHION FOR INHIBITION OF HEN BRAIN ACETYLCHOLINESTERASE AND NEUROTOXIC ESTERASE IN-VITRO

The cholinergic toxicity of malathion is exacerbated by its isomerizat ion product, isomalathion, which inhibits detoxifying carboxylesterase s as well as target acetylcholinesterase (AChE). Previous work has sho wn that the four stereoisomers of isomalathion, (1R, 3R), (1R, 3S), (1 S, 3R), and (1S, 3S), differ in their inhibitory potencies against eit her rat brain or electric eel AChE. The present study examined the rel ative inhibitory potencies of these stereoisomers and the totally race mic mixture (1RS, 3RS) against hen brain AChE and neurotoxic esterase (NTE) to provide new data on stereoselective inhibition of neurotoxico logically significant esterases and to assess the potential of these c ompounds to cause organophosphorus (OP) compound-induced delayed neuro toxicity (OPIDN). The order of potencies against hen brain AChE was (1 R, 3R) > (1R, 3S)>(1RS, 3RS)>(1S, 3R)> (1S, 3S), with a 15-fold differ ence between the strongest (k(i) = 388 mM(-1) min(-1); 20 min I50 = 89 .3 nM) and weakest (k(i) = 25.6 mM(-1) min(-1); 20 min I50 = 1354 nM) inhibitors. Both asymmetric centers contributed substantially and inte rdependently to inhibitory potency, but the effect of changing the con figuration at phosphorus alone was greater than changing the configura tion at carbon alone. None of the isomalathions was an effective inhib itor of hen brain NTE (extrapolated 20 min I50 values were 1.2 to 29 m M, yielding NTE/AChE I50 ratios (neuropathy target ratios, NTRs) of 1. 5 x 10(3) to 1.5 x 10(5). NTRs of this magnitude indicate that none of the isomalathions should initiate OPIDN, even after doses greatly exc eeding the LD50. Therefore, reports of OPIDN or other neuropathic sequ elae associated with malathion exposures in humans cannot be explained on the basis of NTE inhibition by contaminating isomalathions. (C) 19 96 Academic Press, Inc.