STUDIES ON THE EFFECT OF CHLORCYCLIZINE AND OTHER DRUGS ON THE TOXICITY OF SEVERAL ORGANOPHOSPHATE ANTICHOLINESTERASES

¹ Department of Pharmacology, Jefferson Medical College, Philadelphia, Pennsylvania

Several drugs known to affect liver microsomal enzyme systems were studied for their effects on the toxicity of some of the organophosphate insecticides in mice. An attempt was made to explain the effects observed on the basis of changes in the levels of activity of various esterases in the liver and plasma.

Pretreatment of mice daily for 4 days with chlorcyclizine, phenobarbital, SKF-525A or cyclizine produced marked protection against the toxicity of Malathion, Parathion, and EPN. The 4-day chlorcyclizine pretreatment also increased substantially the oral LD50s of paraoxon, TEPP and physostigmine. A single subcutaneous dose of chlorcyclizine (50 mg/kg) gave protection against Parathion beginning in 6 to 12 hours and lasting for approximately 4 days. Twenty-four hours after the administration of phenobarbital or SKF-525A substantial protection against Parathion poisoning was also observed.

The conversion of Parathion to paraoxon by mouse liver was about twice as rapid when the mice were pretreated for 4 days with chlorcyclizine. Forty-eight hours after a single dose of chlorcyclizine serum paraoxonase (A-esterase) activity was markedly lowered while liver paraoxonase activity was slightly elevated. A reduction of plasma paraoxonase activity also occurred after a single dose of phenobarbital or of SKF-525A, the maximum effect being at 48 hours.

The administration of a single dose of 50 mg/kg of chlorcyclizine increased the ratio of liver weight to body weight by 13% in 24 hours. The daily administration of the same dose for 3 days increased the ratio to 31% over the control value at 24 hours after the last dose.

Twenty-four hours after a single dose of chlorcyclizine plasma and liver triacetin esterase activity was markedly elevated, and increased even further when chlorcyclizine was administered for 3 days. An increase in plasma triacetin esterase was also noted 24 hours after phenobarbital and SKF-525A. An increase in proteolytic activity of plasma, indicated by the increased hydrolysis of tosylarginine methyl ester, was observed in mice pretreated 24 hours before with chlorcyclizine, phenobarbital and SKF-525A.

It is concluded that the decrease in the toxicity of the cholinesterase inhibitors tested following the administration of chlorcyclizine, phenobarbital or SKF-525A may be at least partly attributed to the rise in activity of certain esterases of liver and plasma. The increased esterases might be expected to combine with the cholinesterase inhibitors and thus have a sparing effect on the more vital acetylcholinesterase.

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