Carboxylesterases

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

Permethrin, a pyrethrin pesticide, decreased the inhibition of brain cholinesterase activity by methyl parathion, but methyl parathion decreased the LD50 of permethrin when the two pesticides were simultaneously administered to rats (Ortiz et al. 1995). The potentiation of permethrin lethality may be due to the inhibition by methyl parathion of carboxylesterase, which metabolizes permethrin. 

Shi D, Yang J, Yang D, LeCluyse EL, Black C, You L, Akhlaghi F, Yan B (2006) Anti-influenza prodrug oseltamivir is activated by carboxylesterase human carboxylesterase 1, and the activation is inhibited by antiplatelet agent clopidogrel. J Pharmacol Exp Ther 319 1477-1484... 

Types of Carboxylesterase Isolated from Rat Liver Microsomes... 

The microsomal fraction consists mainly of vesicles (microsomes) derived from the endoplasmic reticulum (smooth and rough). It contains cytochrome P450 and NADPH/cytochrome P450 reductase (collectively the microsomal monooxygenase system), carboxylesterases, A-esterases, epoxide hydrolases, glucuronyl transferases, and other enzymes that metabolize xenobiotics. The 105,000 g supernatant contains soluble enzymes such as glutathione-5-trans-ferases, sulfotransferases, and certain esterases. The 11,000 g supernatant contains all of the types of enzyme listed earlier. 

Mammals and some Malathion Carboxylesterase methylenedioxyphenyls Some OPs other than <200... 

In addition to ester bonds with P (Section 10.2.1, Figures 10.1 and 10.2), some OPs have other ester bonds not involving P, which are readily broken by esteratic hydrolysis to bring about a loss of toxicity. Examples include the two carboxylester bonds of malathion, and the amido bond of dimethoate (Figure 10.2). The two carboxylester bonds of malathion can be cleaved by B-esterase attack, a conversion that provides the basis for the marked selectivity of this compound. Most insects lack an effective carboxylesterase, and for them malathion is highly toxic. Mammals and certain resistant insects, however, possess forms of carboxylesterase that rapidly hydrolyze these bonds, and are accordingly insensitive to malathion toxicity. 

A nnmber of other examples are known in which genetically based resistance was dne to enhanced detoxication of OPs. These include malathion resistance in some stored product pests owing to high carboxylesterase activity, and resistance of strains of the housefly to diazinon due to detoxication by specific forms of a glutathione-S-transferase and monooxygenase (Brooks 1972). 

Carboxylesterases Esterases that hydrolyze organic compounds with carboxylester bonds. Carboxylesterases that are inhibited by organophosphates (OPs) belong to the category EC 3.1.1.1 in the lUB classification of enzymes. 

Hosokawa, M., Maki, T., and Satoh, T. (1987). Mnltiphcity and regnlation of hepatic microsomal carboxylesterases in rats. Molecular Pharmacology 31, 579-584. 

Carboxylesterase 3.1.1.1 esters, alcohols alcohols, carboxylic acids, alcohols >100... 

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)-... 

Rivory LP, Bowles MR, Robert J et al. Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), by human liver carboxylesterase. Biochem Pharmacol 1996 52 1103-1111. 

Escartin E, Porte C (1997) The use of cholinesterase and carboxylesterase activities from Mytilus galloprovincialis in pollution monitoring. Environ Toxicol Chem 16(10) 2090-2095... 

Satoh, H. et al., Human anti-endoplasmic reticulum antibodies in sera of patients with halothane-induced hepatitis are directed against a trifluoroacetylated carboxylesterase, Proc. Nat. Acad. Sci. USA, 86, 322, 1989. 

Keywords Carboxylesterase CYP Ester hydrolysis Metabolism Oxidation Pyrethroid... 

In addition, three types of lipophilic conjugates have been found in pyrethroid metabolism studies (Fig. 4). They are cholesterol ester (fenvalerate) [15], glyceride (3-PBacid, a common metabolite of several pyrethroids) [16], and bile acid conjugates (fluvalinate) [17]. It is noteworthy that one isomer out of the four chiral isomers of fenvalerate yields a cholesterol ester conjugate from its acid moiety [15]. This chiral-specific formation of the cholesterol ester has been demonstrated to be mediated by transesterification reactions of carboxylesterase(s) in microsomes, not by any of the three known biosynthetic pathways of endogenous cholesterol esters... 

Extensive metabolism studies carried out mainly in rats and mice show that pyrethroids are metabolized by oxidation and ester cleavage, which are mediated by CYP isoforms and carboxylesterases, respectively. CYP isozymes and carboxylesterases responsible for the metabolism are reviewed below. 

Carboxylesterases (CESs) catalyze hydrolysis of pyrethroids. The expression of CESs is ubiquitous in mammals. The highest hydrolase activity is present in liver. 

Table 1 Cytochrome P450s and carboxylesterases responsible for metabolism of pyrethroids... 

Pyrethroids Cytochrome P450s (CYP) Carboxylesterases (CES) Others References... 

Fig. 6 Seven-compartment PBPK model for deltamethrin Km represents metabolic rate constant (Kml carboxylesterase in blood, Km2 cytochrome P450 in liver, Km3 carboxylesterase in liver, KmFcc rate constant in feces) [49]...

Satoh T, Hosokawa M (2006) Structure, function and regulation of carboxylesterases. Chem Biol Interact 162 195-211... 

Ross MK, Crow JA (2007) Human carboxylesterases and their role in xenobiotic and endobi-otic metabolism. J Biochem Mol Toxicol 21 187-196... 

Munger JS, Shi GP, Mark EA, Chin DT, Gerard C, Chapman HA (1991) A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases. J Biol Chem 266 18832-18838... 

Xu G, Zhang W, Ma MK, McLeod FIL (2002) Human carboxylesterase 2 is commonly expressed in tumor tissue and is correlated with activation of irinotecan. Clin Cancer Res 8 2605-2611... 

Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen EG, Masson P, Lockridge O (2005) Butyrylcholinesterase, paraoxonase, and albumin esterase, but no carboxylesterase, are present in human plasma. Biochem Pharmacol 70 1673-1684... 

Ross MK, Borazjani A, Edwards CC, Potter PM (2006) Hydrolytic metabolism of pyrethroids by human and other mammalian carboxylesterases. Biochem Pharmacol 71 657-669... 

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