These Es1-/- knockout mice lack exon 5 of the carboxylesterase 1C (Ces1c or Es1) gene, abolishing gene function. Mice that are homozygous for this allele are viable, fertile, and normal in size. Carboxylesterases are expressed in the liver and are found in many tissues including the intestine, lung, and in the plasma of mice, but not in the plasma of humans. To mimic the lack of ES1 in human plasma and the resulting increase in susceptibility to nerve agents and to drugs that are hydrolyzed by ES1, these mice have had plasma ES1 activity eliminated. ES1 acts as an organophosphorus (OP) bioscavenger which reduces the level of OP reaching biologically relevant targets and protects against lethal toxicity from nerve agents. Es1-/- mice have normal acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and paraoxonase plasma activity, with normal levels of carboxylesterase activity in other tissues, including the brain, lungs, liver, intestines, and heart. These mutant mice react in a similar manner as control mice to some low toxicity OP agents, such as cyclosarin thiocholine analog and tabun, and are protected against some nerve agents, such as chlorpyrifos and chlorpyrifos oxon. They also display increased sensitivity to soman coumarin as noted by decreased body temperature and increased morbidity. These mice may be useful as a model in which to measure and protect against nerve agents and for testing drugs that are hydrolyzed by ES1.
