THE MAMMALIAN CARBOXYLESTERASES - FROM MOLECULES TO FUNCTIONS

Citation
T. Satoh et M. Hosokawa, THE MAMMALIAN CARBOXYLESTERASES - FROM MOLECULES TO FUNCTIONS, Annual review of pharmacology and toxicology, 38, 1998, pp. 257-288
Citations number
186
Categorie Soggetti
Toxicology,"Pharmacology & Pharmacy
ISSN journal
03621642
Volume
38
Year of publication
1998
Pages
257 - 288
Database
ISI
SICI code
0362-1642(1998)38:<257:TMC-FM>2.0.ZU;2-Q
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 beh avior of most therapeutic agents containing ester or amide bonds. Carb oxylesterase activity can be influenced by interactions of a variety o f compounds either directly or at the level of enzyme regulation. Sinc e a significant number of drugs are metabolized by carboxylesterase, a ltering the activity of this enzyme class has important clinical impli cations. Drug elimination decreases and the incidence of drug-drug int eractions increases when two or more drugs compete for hydrolysis by t he same carboxylesterase isozyme. Exposure to environmental pollutants or to lipophilic drugs can result in induction of carboxylesterase ac tivity. Therefore, the use of drugs known to increase the microsomal e xpression of a particular carboxylesterase, and thus to increase assoc iated 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 comparis on of the nucleotide and amino acid sequence of the mammalian carboxyl esterases 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 scien tific community in regards to a systematic nomenclature and classifica tion of mammalian carboxylesterase. Until recently, adequate sequence information has not been available such that valid links among the mam malian carboxylesterase gene family or evolutionary relationships coul d be established. However, sufficient basic data are now available to support such a novel classification system.