Biochemical Mechanisms of Organophosphate Tolerance

摘要

The lethality of organophosphate cholinesterase inhibitors is thought to result from depression of the respiratory center in the brain stem, construction of and increased secretion by the airways, and paralysis of the respiratory musculature. While tolerance to the cholinergic toxicity of organophosphates has been well documented, such studies have not included investigations of the brain stem and extrapulmonary airways. In this report tolerance in mice to the insecticide malathion and in rats to Diisopropyflurophoshate (DFP) is demonstrated. At 24 hr after 14 daily doses of malathion (400 mg/kg, ip), CHE activities were 27, 26 and 28% of control in striatum (ST), hippocampus (HI) and cortex (CX), respectively while brain stem (BS) CHE activity was 41% of control. In addition, the numbers of muscarinic receptors (Bmax) decreased 30, 20, and 22% in ST, HI, and CX, respectively. In contrast, there was no change in BS Bmax. Male rats were injected, sc with DFP over 14 days. Diminished signs of toxicity and return to normal weight gain indicated tolerance. The lack of parallelism between CHE inhibition and Bmax effects in brain stem as compared to all other tissues tested raises questions as to the mechanism(s) by which the respiratory system adapts during repeated OP exposure. The lesser amount of CHE inhibition in select brain regions may be mechanistically involved in OP tolerance. (AW)