Structure, Function, and Regulation of Carboxylesterases

The chapter deals primarily with the characteristics and the molecular cloning of the individual, recently identified carboxylesterases (CarbE) isozymes. The mammalian CarbEs comprise a multigene family whose gene products are localized in the endoplasmic reticulum (ER) of many tissues. These enzymes efficiently catalyze the hydrolysis of a variety of ester- and amide-containing chemicals as well as drugs (including prodrugs) to the respective free acids. They are involved in detoxification or metabolic activation of various drugs, environmental toxicants, and carcinogens. Carboxylesterases also catalyze the hydrolysis of endogenous compounds, such as short- and long-chain acyl-glycerols, long-chain acyl-carnitine, and long-chain acyl-CoA esters. Characteristics of CarbEs are reviewed in relation to the metabolism of xenobiotics. Multiple isozymes of hepatic microsomal CarbE exist in various animal species, and some of these isozymes are involved in the metabolic activation of certain carcinogens, as well as being associated with hepatocarcinogenesis. The expression of CarbEs is ubiquitous, with high levels in the liver, small intestine, kidney, and lung. CarbEs show such a broad range of substrate specificity that they can be involved in detoxification or biotransformation of many kinds of drugs, as well as endogenous fatty acid esters. It has been suggested that CarbEs can be classified into four major groups according to the homology of the amino acid sequence, and a majority of CarbEs that have been identified belong to the CES1 or CES2 family.