Studies of choline acetylase inhibition by DDA (dichlorodiphenylacetic acid) and its possible relationship to DDT toxicity

Abstract

The effect of DDA, a metabolite of DDT, on rabbit intestinal motility in vitro, on the patellar reflex, and on a choline acetylase system was studied. Na-DDA was found to inhibit the pendular activity of rabbit small intestine at a minimal bath concentration of 10 −4 M. Exposure to 10 −3 M DDA completely blocked rhythmic activity and depressed intestinal tone. The activity could be restored by washing or by exposure to 10 −8 acetylcholine, 5 × 10 −8 physostigmine, or 2 × 10 −8 TEPP. The induction of peristaltic activity by physostigmine or TEPP was partially inhibited or completely blocked by prior treatment with DDA. A method for the injection of drugs directly to the lumbar spinal cord via a lumbar artery is described. DDA injected by this route in a coconut oil emulsion in doses between 0.4 and 1.8 mg facilitated the patellar reflex response. Doses larger than 2 mg depressed the patellar reflex. When the patellar reflex was depressed, spontaneous activity could be momentarily restored by acetylcholine or acetylcholine + TEPP similarly injected. Pantothenyl alcohol by this route gave a weak restoration of the reflex response. Diphenylylethylacetic acid and diphenylylamylacetic acid, known choline acetylation inhibitors, produced effects similar to those of DDA. Acetylcholine synthesis by an in vitro system utilizing acetone-dried brain powder as a source of choline acetylase was depressed by Na-DDA. When Ac-CoA was used as a substitute for ATP + CoA in this system, the level of acetylcholine synthesis was diminished but there was little inhibition by Na-DDA. The results indicate that the acetate activating step is the principal site of the block. The effects of DDA on intestinal motility and the patellar reflex are interpreted on the basis of inhibition of the acetate-activating step. Other alternative possible hypotheses are discussed. The possible relationship of these findings to the problem of DDT intoxication is discussed.