Alteration of hepatic carboxylesterase activity by soman: inhibition in vitro and enhancement in vivo.
1. Hydrolysis of the drug esters procaine, chloramphenicol succinate, and prednisolone succinate was studied. Addition of soman to guinea pig liver microsomes caused a dose-dependent inhibition of hydrolysis of all three substrates; at the highest soman concentration (1 microM), ester hydrolysis was totally abolished. 2. Ester hydrolysis was also measured in liver microsomes from guinea pigs pretreated with soman at a low dose (10% of LD50) or at a high dose (90% of LD50) either 1 h or 12 h before killing. Plasma-cholinesterase activity was decreased in all pretreated animals. Liver carboxylesterase activity, measured with the three drug substrates and by hydrolysis of 4-nitrophenyl acetate was increased by all pretreatments. 3. This enhancing effect varies with the substrate and increases with dose of soman. The 12 h pretreatment produced a greater increase in activity than did the 1 h pretreatment. 4. These studies indicate that soman is a potent inhibitor of carboxylesterase activity in vitro but increases the activity of the liver enzyme when administered in vivo.
Castle
M C
MC
Department of Pharmacology, Eastern Virginia Medical School, Norfolk 23501.
D000818:Animals; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002701:Chloramphenicol / Q000031:analogs & derivatives / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004789:Enzyme Activation / Q000187:drug effects; D006168:Guinea Pigs; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D011239:Prednisolone / Q000031:analogs & derivatives / Q000378:metabolism; D011343:Procaine / Q000378:metabolism; D012999:Soman / Q000494:pharmacology*
D011343:Procaine; D002701:Chloramphenicol; D012999:Soman; D011239:Prednisolone; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase; C021322:prednisolone hemisuccinate; C026016:chloramphenicol succinate