THE ROLE OF CYTOCHROME P-450 INHIBITION IN THE LOW MAMMALIAN TOXICITY OF FENITROTHION (PESTICIDE, METABOLISM)
Abstract
Fenitrothion, an organophosphate (OP) insecticide, has a very low mammalian toxicity when compared with that of the structurally similar methyl parathion. The explanation for the striking difference has eluded investigators for 25 years. The present research was initiated to determine the reasons for the 50-fold difference in mouse oral LD's for methyl parathion and fenitrothion. Experiments were conducted to determine the effects of fenitrothion dosing on several metabolic and pharmacologic parameters in various tissues. These parameters included cholinesterase activity, tissue levels of fenitrothion and its metabolites, cytochrome P-450 activity, and metabolism of fenitrothion and fenitrooxon. Within minutes of fenitrothion dosing, tissue cholinesterase activity declines greatly, and typical OP signs of poisoning are observed. Fenitrooxon levels in the liver displayed an unexpected biphasic pattern, rising and falling, then rising again within 2 hours. The sharp drop after 1 hour was attributed to inhibition of cytochrome P-450 by sulfur released during the metabolism of fenitrothion to fenitrooxon. Another novel finding was the differential inhibition of the two principal MFO pathways for fenitrothion following fenitrothion treatment. This resulted in severe inhibition of the activation pathway but much less inhibition of the detoxification pathway. Similar differential inhibition of fenitrothion metabolism in vitro was observed following treatment with other thiono compounds such as carbon disulfide and other phosphorothionate pesticides. It was concluded that one of the major factors determining fenitrothion's mammalian toxicity is the differential inhibition of cytochrome P-450 isozymes whereby fenitrooxon production is greatly reduced while detoxification of fenitrothion and fenitrooxon continues. In addition, others have suggested that non-specific binding in some tissues (primarily the liver) may initially trap much of the oxygen analog produced. Although the toxicology of fenitrothion has proven to be unexpectedly complex, some of the conclusions from this work may be applicable to other OP compounds of low mammalian toxicity where the oxygen analog is of sufficiently low toxicity that high doses of the phosphorothionate can be tolerated.
Degree
Ph.D.
Subject Area
Pharmacology
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