Structural requirements for altering the L-tryptophan metabolism in mice by organophosphorous and methylcarbamate...

This study defined structural requirements for organophosphorous and methylcarbamate insecticides for altering the L-kynurenine pathway of L-tryptophan metabolism in mice. Kynurenine formamidase inhibition by organophosphorous acid triesters and methylcarbamates is the proposed primary event resulting in increase in xanthurenic acid urinary excretion and plasma L-kynurenine. Alteration of the L-kynurenine pathway occurred with compounds that inhibited liver kynurenine formamidase by more than 80%. Pyrimidinyl phosphorothioates followed by crotonamide phosphates were the most potent compounds that changed L-tryptophan metabolism, i.e., pirimiphos-ethyl (20 mg/kg) inhibited liver kynurenine formamidase by 99%, and increased xanthurenic acid urinary excretion and plasma L-kynurenine by 576 +/- 195 and 330 +/- 44%, respectively. Replacement of sulphur by oxygen in the phosphorothioate diazinon reduced in vivo liver kynurenine formamidase inhibition. Consequently, xanthurenic acid urinary excretion and plasma L-kynurenine were not elevated. Atropine, cycloheximide, 2-PAM and phenylmethylsulfonyl fluoride did not alleviate diazinon-altered L-tryptophan metabolism. Because of the potential of the majority of organophosphorous acid triesters and methylcarbamates to inhibit kynurenine formamidase, this novel noncholinergic mechanism warrants consideration in assessment of organophosphorous and methylcarbamate toxicity in occupational and accidental exposures.