Triorthotolyl phosphate inhibition of carboxylesterases and potentiation of procaine toxicity

Abstract

Groups of mice were given single doses of triorthotolyl phosphate (TOTP) (1–125 mg/kg, i.p.) 18hr prior to sacrifice or procaine challenge. A dose-dependent decrease was recorded in liver carboxylesterase hydrolysis of diethyl succinate, triacetin and procaine. TOTP pretreatment shortened the time to onset and prolonged the duration of procaine (175 mg/kg, i.p.)-induced loss of righting ability. The correlation coefficient for inhibition of liver procaine hydrolysis and prolongation of procaine action was 0.97 (P < 0.0001). No deaths were observed in procaine-injected controls yet mortality after procaine injection in TOTP-pretreated mice increased as a function of the TOTP pretreatment dose. In addition, plasma procaine concentrations after procaine injection (150 mg/kg, i.p.) reached peak levels sooner, remained elevated longer and were 3-fold higher in the TOTP-pretreated mice as compared to corn oil-pretreated procaine-injected controls. Results demonstrate potentiation of procaine toxicity by TOTP and suggest that this results from inhibition of procaine metabolism in vivo.