Enhancement of hepatic microsomal esterase activity following soman pretreatment in guinea pigs.
Soman (pinacolyl methylphosphonofluoridate), a highly toxic organophosphate compound, has been found to be a strong inhibitor of hepatic microsomal carboxylesterase in vitro, but an enhancer of carboxylesterase when administered in vivo. In response to this paradoxical observation, the objective of this study was to determine if soman could cause true enhancement of the metabolism of drugs in the guinea pig and, if so, to characterize the enhanced enzyme activity. Following the pretreatment of guinea pigs with 90% LD50 soman, enhancement of microsomal esterase activity was noted 12 and 24 hr after pretreatment. Using Michaelis-Menten enzyme kinetic studies, enhancement was found to occur with liver carboxylesterase and procaine esterase, but not with aniline hydroxylase. Since the soman-enzyme complex was known to undergo aging with the release of pinacolyl alcohol and the subsequent formation of pinacolone, the effects of these metabolites on the activity of liver microsomal enzymes in vitro were explored. Pinacolone and pinacolyl alcohol produced enzyme enhancement in vitro in a manner similar to that produced by soman pretreatment. These effects were compared with those made by acetone in the same incubations, since the enhancing influence 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 the activities of the same liver microsomal enzymes were studied following pretreatment of the guinea pigs with 90% LDLo (lowest published lethal dose) pinacolone. Pretreating guinea pigs with pinacolone prior to killing them enhanced liver microsomal carboxylesterase and procaine esterase activities, but had no effect on microsomal aniline hydroxylase activity. This pattern of enzyme enhancement was similar to that observed after soman pretreatment. Therefore, soman was found to enhance hepatic microsomal esterase activity in the guinea pig in a manner similar to that seen with its metabolites, as well as acetone. This information may give insight into how the efficacy and toxicity of therapeutic drugs, other xenobiotics, and endogenous materials may be altered in individuals who survive an exposure to soman.
Luttrell
W E
WE
Department of Pharmacology, Eastern Virginia Medical School, Norfolk 23501.
Castle
M C
MC
D000096:Acetone / Q000494:pharmacology; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D002074:Butanones / Q000494:pharmacology; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004950:Esterases / Q000378:metabolism*; D006168:Guinea Pigs; D000441:Hexanols / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D012680:Sensitivity and Specificity; D012999:Soman / Q000494:pharmacology*
D002074:Butanones; D000441:Hexanols; D000096:Acetone; C084935:pinacolone; C053516:3,3-dimethyl-2-butanol; D012999:Soman; D000815:Aniline Hydroxylase; D004950:Esterases; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase