Inhibition of hepatic microsomal carboxylesterase activity by paraoxon.

A large number of therapeutic agents are esters of carboxylic acids and are thus substrates for microsomal carboxylesterase enzymes. These studies characterized the effects of the organophosphate compound, paraoxon, on the hydrolysis of several drug esters (procaine, chloramphenicol succinate, prednisolone succinate, lidocaine, procainamide and methylparaben) by microsomal preparations from guinea-pigs. These investigations demonstrate that carboxylesterase activity toward several drug esters is present in liver, lung and kidney. The liver is by far the major site of hydrolysis of these ester compounds. Since no hydrolysis was observed with the two amide esters, the hydrolysis of carboxylesters and amide esters appears to be mediated by different enzymes in the guinea-pig. At the substrate concentrations studied, the hydrolysis of methylparaben followed zero-order kinetics. When added to isolated microsomal preparations, paraoxon produced a dose-dependent inhibition of hydrolysis of all substrates. Administration of paraoxon to guinea-pigs prior to isolation of microsomes did not produce consistent effects with any substrate. Inhibition of ester hydrolysis was observed with some pretreatments, while either no change or increased hydrolysis was observed with other pretreatment regimens.