THE MAMMALIAN CARBOXYLESTERASES: From Molecules to Functions

Abstract

Multiple carboxylesterases (EC 3.1.1.1) play an important role in the hydrolytic biotransformation of a vast number of structurally diverse drugs. These enzymes are major determinants of the pharmacokinetic behavior of most therapeutic agents containing ester or amide bonds. Carboxylesterase activity can be influenced by interactions of a variety of compounds either directly or at the level of enzyme regulation. Since a significant number of drugs are metabolized by carboxylesterase, altering the activity of this enzyme class has important clinical implications. Drug elimination decreases and the incidence of drug-drug interactions increases when two or more drugs compete for hydrolysis by the same carboxylesterase isozyme. Exposure to environmental pollutants or to lipophilic drugs can result in induction of carboxylesterase activity. Therefore, the use of drugs known to increase the microsomal expression of a particular carboxylesterase, and thus to increase associated drug hydrolysis capacity in humans, requires caution. Mammalian carboxylesterases represent a multigene family, the products of which are localized in the endoplasmic reticulum of many tissues. A comparison of the nucleotide and amino acid sequence of the mammalian carboxylesterases shows that all forms expressed in the rat can be assigned to one of three gene subfamilies with structural identities of more than 70% within each subfamily. Considerable confusion exists in the scientific community in regards to a systematic nomenclature and classification of mammalian carboxylesterase. Until recently, adequate sequence information has not been available such that valid links among the mammalian carboxylesterase gene family or evolutionary relationships could be established. However, sufficient basic data are now available to support such a novel classification system.

Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I

“…This is a poorly characterized secretory protein with lipid-mobilizing properties, which in rats is mainly expressed in the liver although it is widely distributed in human tissues [35,38]. Other metabolic gene whose expression was strongly induced in the cirrhotic liver was the phenobarbital-inducible form of the carboxylesterases, a large family of proteins involved in drug metabolism [39]. This response was consistent with the protocol used in this work for the induction of cirrhosis, in which phenobarbital is continuously administered in drinking water.…”

Characterization of pyrethroid hydrolysis by the human liver carboxylesterases hCE-1 and hCE-2

“…These mouse carboxylesterases are highly similarity to two major human carboxylesterase isozymes, human carboxylesterase (hCE 1 )-1 and hCE-2 at the amino acid sequence level. hCE-1 and hCE-2 are known as α/β-hydrolase fold proteins that play major roles in the metabolism of a wide variety of exogenous ester-containing compounds, including numerous pharmaceuticals and pesticides [7]. From these facts, we hypothesize that hCE-1 and hCE-2 are involved in pyrethroid hydrolysis.…”

“…From our results, hCE-1 and hCE-2 seemed to possess strong and opposite selectivities for (αS) (1R)-trans-A3 and (2R)(αS)-A4, respectively. Because hCE-1 and hCE-2 are involved in the activation of prodrugs, inactivation of ester-containing pharmaceuticals, and metabolism of xenobiotics [7], it is of great importance to predict a prodrug/xenobiotics response in individuals. These fluorescent substrates are thus exceptionally useful for the evaluation of the relative amounts of specific carboxylesterase isozymes.…”

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun,

“…Carboxylesterases (CEs; EC 3.1.1.1) are members of the same serine [22][23][24]. This glycoprotein shares 34% identity and 1.2 Å rmsd over Cα positions with AcChE, and utilizes the same two-step serine hydrolase catalytic mechanism.…”