ENHANCEMENT OF HEPATIC-MICROSOMAL ESTERASE-ACTIVITY FOLLOWING SOMAN PRETREATMENT IN GUINEA-PIGS

Soman (pinacolyl methylphosphonofluoridate), a highly toxic organophos phate compound, has been found to be a strong inhibitor of hepatic mic rosomal carboxylesterase in vitro, but an enhancer of carboxylesterase when administered in vivo. In response to this paradoxical observatio n, the objective of this study was to determine if soman could cause t rue enhancement of the metabolism of drugs in the guinea pig and, if s o, to characterize the enhanced enzyme activity. Following the pretrea tment of guinea pigs with 90% LD(50) soman, enhancement of microsomal esterase activity was noted 12 and 24 hr after pretreatment. Using Mic haelis-Menten enzyme kinetic studies, enhancement was found to occur w ith liver carboxylesterase and procaine esterase, but not with aniline hydroxylase. Since the soman-enzyme complex was known to undergo agin g with the release of pinacolyl alcohol and the subsequent formation o f pinacolone, the effects of these metabolites on the activity of live r microsomal enzymes in vitro were explored. Pinacolone and pinacolyl alcohol produced enzyme enhancement in vitro in a manner similar to th at produced by soman pretreatment. These effects were compared with th ose made by acetone in the same incubations, since the enhancing influ ence of acetone has already been well documented. Similarity was found between the in vitro effects of acetone and the effects of pinacolone and pinacolyl alcohol. Lastly, the in vivo effects of pinacolone on t he activities of the same liver microsomal enzymes were studied follow ing pretreatment of the guinea pigs with 90% LD(Lo) (lowest published lethal dose) pinacolone. Pretreating guinea pigs with pinacolone prior to killing them enhanced liver microsomal carboxylesterase and procai ne esterase activities, but had no effect on microsomal aniline hydrox ylase activity. This pattern of enzyme enhancement was similar to that observed after soman pretreatment. Therefore, soman was found to enha nce hepatic microsomal esterase activity in the guinea pig in a manner similar to that seen with its metabolites, as well as acetone. This i nformation may give insight into how the efficacy and toxicity of ther apeutic drugs, other xenobiotics, and endogenous materials may be alte red in individuals who survive an exposure to soman.