Carboxylesterases intestinal

Drugs may also undergo hydrolysis by intestinal esterases (hydrolases), more specifically carboxylesterases (EC 3.1.1.1) in the intestinal lumen and at the brush border membrane [58, 59]. It has been shown that intestinal hydrolase activity in humans was closer to that of the rat than the dog or Caco-2 cells [60]. In these studies, six propranolol ester prodrugs and p-nitrophenylacetate were used as substrates, and the hydrolase activity found was ranked in the order human > rat Caco-2 cells > dog for intestinal microsomes. The rank order in hydrolase activity for the intestinal cytosolic fraction was rat > Caco-2 cells = human > dog. The hydrolase activity towards p-nitrophenylacetate and tenofovir disoproxil has also been reported in various intestinal segments from rats, pigs and humans. The enzyme activity in intestinal homogenates was found to be both site-specific (duodenum > jejunum > ileum > colon) and species-dependent (rat > man > Pig)-... 

Crow JA, Borazjani A, Potter PM, Ross MK (2007) Hydrolysis of pyrethroids by human and rat tissues examination of intestinal, liver and serum carboxylesterases. Toxicol Appl Pharmacol 221 1-12... 

Cauxin is markedly different from previously reported mammalian CESs in term of urinary excretion. Other mammalian CESs comprise multigene families, and CES isozymes are highly and ubiquitously expressed in tissues such as the brain, liver, kidney, lung, and small intestine (Satoh and Hosokawa 1998). Our work on cauxin was the first description of a carboxylesterase excreted in urine. 

In humans, erythrocytes contain an esterase that displays genetic polymorphism [86], This esterase has been called esterase D (ES-D), a name without connection to the above-presented A-, B-, and C-classification. Three carboxylesterases named HU1, HU2, and HU3 have been found in human liver microsomes. Other tissues where esterases have been found include brain, plasma, stomach, small intestine, and colon [79]. 

Carboxylesterases (EC 3.1.1.1) can be detected in most mammalian tissues. Besides organs with high carboxylesterase activity such as liver, kidney, and small intestine, esterase activity is present, e.g., in the brain, nasal mucosa, lung, testicle, and saliva. Compared to rat plasma, human plasma contains little carboxylesterase, its esterase activity being essentially due to cholinesterase [61][73][79][89-91],... 

The intracellular localization of carboxylesterases is predominantly microsomal, the esterases being localized in the endoplasmic reticulum [73] [79] [93], They are either free in the lumen or loosely bound to the inner aspect of the membrane. The carboxylesterases in liver mitochondria are essentially identical to those of the microsomal fraction. In contrast, carboxylesterases of liver lysosomes are different, their isoelectric point being in the acidic range. Carboxylesterase activity is also found in the cytosolic fraction of liver and kidney. It has been suggested that cytosolic carboxylesterases are mere contaminants of the microsomal enzymes, but there is evidence that soluble esterases do not necessarily originate from the endoplasmic reticulum [94], In guinea pig liver, a specific cytosolic esterase has been identified that is capable of hydrolyzing acetylsalicylate and that differs from the microsomal enzyme. Also, microsomal and cytosolic enzymes have different electrophoretic properties [77]. Cytosolic and microsomal esterases in rat small intestinal mucosa are clearly different enzymes, since they hydrolyze rac-oxazepam acetate with opposite enantioselectivity [95], Consequently, studies of hydrolysis in hepatocytes reflect more closely the in vivo hepatic hydrolysis than subcellular fractions, since cytosolic and microsomal esterases can act in parallel. 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

The in vivo metabolism of capecitabine (1) to the active tumor cytotoxic substance 5-fluorouracil (5) is now fairly well understood. When capecitabine is administered orally it is delivered to the small intestine, where it is not a substrate for thymidine phosphorylase in intestinal tissue, and so passes through the intestinal mucosa as an intact molecule and into the bloodstream. When 1 reaches the liver, the carbamate moiety is hydrolyzed through the action of carboxylesterase enzymes, liberating 5 -deoxy-5-fluorocytidine (5 -DFCR, 10). DFUR is partially stable in systemic circulation, but eventually diffuses into tumor cell tissue where it is transformed into 5 -deoxy-5-fluorouridine (5 -DFUR, 9) by cytidine deaminase, an enzyme present in high concentrations in various types of human cancers compared to adjacent healthy cells (although it is present in significantly lower levels in the liver). Within the tumor, 5-... 

Wadkins RM, Hyatt JL, Yoon KJ, Morton CL, Lee RE, Damodaran K, et al. Discovery of novel selective inhibitors of human intestinal carboxylesterase for the amelioration of irinotecan-induced diarrhea Synthesis, quantitative structure-activity relationship analysis, and biological activity. Mol Pharmacol 2004 65 1336—43. 

Taketani, M., Shii, M., Ohura, K., Ninomiya, S. and Imai, T. (2007) Carboxylesterase in the liver and small intestine of experimental animals and human. Life Sciences, 81, 924-932. 

Khanna, R., Morton, C.L., Danks, M.K. and Potter, P.M. (2000) Proficient metabolism of irinotecan by a human intestinal carboxylesterase. Cancer Research, 60, 4725-4728. 

Schwer, H., Langmann, T., Daig, R., Becker, A., Aslanidis, C., and Schmitz, G. 1997, Molecular cloning and characterization of a novel putative carboxylesterase, present in human intestine and liver, Biochem. Biophys. Res. Commun., vol. 233, no. 1, pp. 117-120. 

Plasma butylcholinesterase hydrolyzes several simple esters and amides, while plasma paraoxonase hydrolyzes lactone substructures in drugs (Satoh and Hosokawa, 2006). Intestinal and liver microsomal carboxylesterases hydrolyze a variety of esters, amides, and related structures ... 

Lipases a group of carboxylesterases, which preferentially hydrolyse emulsifi neutral fats to fatty acids and glycerol or monoacylglycerols. Calcium ions are required for activity. Pancreatic L. also requires taurocholate. Pancreas and certain plant seeds (e.g. Ricinus) contain particularly high activities of L.In addition, high activities are found in adipose tissue, in the stomach (especially in unweaned infants) and in the liver. Pancreatic L. has M, 35,000. Rapid removal of the third and last fatty acid residue from mixed triacylglycerols is catalysed by a specific mono-acylglycerol lipase (EC 3.1.1.23) produced by the intestinal mucosa. 

Human intestinal microsomes effectively hydrolyzed frans-permethrin however, bioresmethrin, and deltamethrin were not metabolized in the intestine to any appreciable extent. Human hepatic microsomes and cytosol contained both hCE-1 and hCE-2 when examined by native PAGE (polyacrylamide gel electrophoresis) human intestine contained only hCE-2. Table 8 gives the kinetic parameters obtained by Crow et al. (2(X)7) with tranr-permethrin and liver and intestinal carboxylesterases. 

Table 8 Kinetic parameters of trani-permethiin hydrolysis catalyzed by human and rat hepatic subcellular fractions (microsomes and cytosols) and intestinal carboxylesterases...

Balance and tissue retention study. J Agric Food Chem 29 130-135 Crawford MJ, Croucher A, Hutson DH (1981b) The metabolism of the pyrethroid insecticide cypermethrin in rats excreted metabolites. Pestic Sci 12 399-411 Crow JA, Borazjani A, Potter PM, Ross MK (2007) Hydrolysis of pyrethroids by human and rat tissues examination of intestinal, liver and serum carboxylesterases. Toxicol Appl Pharmacol 221 1-12... 

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