Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38

Charasson, Virginie; Bellott, Ricardo; Meynard, Delphine; Longy, Michel; Gorry, Philippe; Robert, Jacques

doi:10.1016/j.clpt.2004.08.007

Cited by 66 publications

(43 citation statements)

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“…NM_001025194 and NM_003869, respectively). Recently, numerous single nucleotide polymorphisms have been identified in hCE-1 and hCE-2 [16][17][18]. So far, none of these polymorphisms have been shown to directly affect esterase activity or expression, and the variability in carboxylesterase activity is thought to be more likely of environmental rather than genetic origin [18].…”

Section: Preparation Of Recombinant Human Carboxylesterasesmentioning

confidence: 99%

“…Recently, numerous single nucleotide polymorphisms have been identified in hCE-1 and hCE-2 [16][17][18]. So far, none of these polymorphisms have been shown to directly affect esterase activity or expression, and the variability in carboxylesterase activity is thought to be more likely of environmental rather than genetic origin [18]. Although the existence of these types of polymorphisms in hCE-1 and hCE-2 are not unexpected, the relative roles that these polymorphisms play in the metabolism of xenobiotics such as pyrethroids and prodrugs are still unclear.…”

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

Nishi

Huang

Kamita

et al. 2006

Archives of Biochemistry and Biophysics

105

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Carboxylesterases hydrolyze a large array of endogenous and exogenous ester-containing compounds, including pyrethroid insecticides. Herein, we report the specific activities and kinetic parameters of human carboxylesterase (hCE)-1 and hCE-2 using authentic pyrethroids and pyrethroid-like, fluorescent surrogates. Both hCE-1 and hCE-2 hydrolyzed type I and II pyrethroids with strong stereoselectivity. For example, the trans-isomers of permethrin and cypermethrin were hydrolyzed much faster than corresponding cis-counterparts by both enzymes. Kinetic values of hCE-1 and hCE-2 were determined using cypermethrin and 11 stereoisomers of the pyrethroid-like, fluorescent surrogates. K m values for the authentic pyrethroids and fluorescent surrogates were in general lower than those for other ester-containing substrates of hCEs. The pyrethroid-like, fluorescent surrogates were hydrolyzed at rates similar to the authentic pyrethroids by both enzymes, suggesting the potential of these compounds as tools for high throughput screening of esterases that hydrolyze pyrethroids. KeywordsCarboxylesterase; Pyrethroid; Fluorescent substrate Synthetic pyrethroid insecticides represented about 17% of the global pesticide market in 2002 [1]. In the coming years, the use of pyrethroids is predicted to further increase with the phase out of the use of organophosphorus insecticides. Additionally, due to the emergence and reemergence of mosquito-vectored diseases such as West Nile fever, Japanese encephalitis, and dengue fever, pyrethroids are being used with increased frequency against adult mosquitoes * Corresponding author. Fax: +1 530 752 1537.E-mail address: bdhammock@ucdavis.edu (B.D. Hammock). NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [2]. Because of the increased agricultural and residential usage of pyrethroids, human exposure to these compounds is also expected to increase.Pyrethroids are ester-containing compounds consisting of various acid and alcohol moieties. Type I pyrethroids are esters of primary alcohols, whereas type II pyrethroids are esters of secondary alcohols that contain a cyano group at the α-carbon of the alcohol moiety. Chiral centers can exist in both the acid and alcohol moieties, leading to the existence of several stereoisomers for each pyrethroid. Ester hydrolysis by carboxylesterases and oxidation by cytochrome P450s are the main detoxification routes of pyrethroids in animals [3]. Differences in the activities of carboxylesterases and P450s between mammals and insects contribute to the low mammalian toxicity of pyrethroids (i.e., pyrethroids are metabolized faster in mammals than in insects) [3]. In general, whole animals or liver microsomes have been used to study pyrethroid metabolism in mammals, and little has been done to identify the specific carboxylesterase isozymes that hydrolyze pyrethroids [4]. Butte and Kemper [5]have shown ester-hydrolytic activities in human serum using pyrethroid-like colorimetric substrates that are not hydrolyzed by acylesterase, ...

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Section: Preparation Of Recombinant Human Carboxylesterasesmentioning

confidence: 99%

mentioning

confidence: 99%

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

Nishi

Huang

Kamita

et al. 2006

Archives of Biochemistry and Biophysics

105

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confidence: 99%

“…This result might be caused by genetic polymorphisms, such as single nucleotide polymorphisms (SNPs) in the CES2 gene. Several SNPs and haplotypes have been reported for the CES2 gene (Charasson et al, 2004;Marsh et al, 2004;Wu et al, 2004), and large ethnic differences in CES2 SNP frequencies are found among Europeans, Africans, and Asian-Americans (Marsh et al, 2004).Previously, 12 exons and their flanking regions of CES2 were sequenced from 153 Japanese subjects, who received irinotecan or steroidal drugs, and 12 novel SNPs, including the nonsynonymous SNP, 100CϾT (Arg 34 Trp), and the SNP at the splice acceptor site of intron 8 (IVS8-2AϾG) were found (Kim et al, 2003). In vitro functional characterization of these SNPs and an additional nonsynonymous SNP, 424GϾA (Val 142 Met), suggested that the 34 Trp and 142 Met variants were defective, and that IVS8-2G might be a lowactivity allele (Kubo et al, 2005).…”

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Haplotypes and a Novel Defective Allele of CES2 Found in a Japanese Population

Kim

Sai²,

Tanaka-Kagawa³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Human carboxylesterase 2 (hCE-2) is a member of the serine esterase superfamily and is responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. hCE-2 also activates an anticancer drug, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin, CPT-11), into its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). In this study, a comprehensive haplotype analysis of the CES2 gene, which encodes hCE-2, in a Japanese population was conducted. Human carboxylesterases are members of the serine esterase superfamily and are responsible for hydrolysis of a wide variety of xenobiotic and endogenous esters. They metabolize esters, thioesters, carbamates, and amides to yield soluble acids and alcohols or amines (Satoh and Hosokawa, 1998;Satoh et al., 2002). In the human liver, two major isoforms of carboxylesterase, hCE-1 and hCE-2, have been identified (Shibata et al., 1993;Schwer et al., 1997). hCE-2 is a 60-kDa monomeric enzyme with a pI value of approximately 4.9 and shares 48% amino acid sequence identity with hCE-1 (Pindel et al., 1997;Schwer et al., 1997;Takai et al., 1997). The CES2 gene, which encodes hCE-2, is located on chromosome 16q22.1 and consists of 12 exons. Distribution of hCE-2 is relatively limited to several tissues, such as the small intestine, colon, heart, kidney, and liver, whereas hCE-1 is ubiquitously expressed (Satoh et al., 2002;Xie et al., 2002).Although both hCE-1 and hCE-2 show broad substrate specificities, hCE-2 is relatively specific for heroin, cocaine (benzoyl ester), 6-acetylmorphine, procaine, and oxybutynin (Pindel et al., 1997;Takai et al., 1997;Satoh et al., 2002). In addition, hCE-2 is reported to play a major role in the metabolic activation of the antitumor drug irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11). Irinotecan is a water-soluble derivative of the plant alkaloid camptothecin and is widely used for treatment of several types of cancer. Irinotecan is converted to 7-ethyl-10-hydroxy- camptothecin (SN-38), a topoisomerase inhibitor, by carboxylesterases (Humerickhouse et al., 2000) and further conjugated by hepatic uridine diphosphate glucuronosyltransferase to form the inactive metabolite SN-38 glucuronide (SN-38G) (Iyer et al., 1998). To a lesser extent, irinotecan is also converted to 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin and 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin by cytochrome P450 3A4 (Dodds et al., 1998;Santos et al., 2000). Irinotecan and its metabolites are excreted by the efflux transporters, ABCB1 (P-glycoprotein), ABCC2 (canalicular multispecific organic anion transporter), and ABCG2 (breast cancer resistance protein), via a hepatobiliary pathway (Mathijssen et al., 2001). Although irinotecan metabolism is rather complex, hCE-2 is a key enzyme that determines the plasma levels of the active metabolite SN-38. Hepatic hCE-2 activity toward irinotecan varies 3-fold in microsomes obtained from a panel of human ...

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“…Irinotecan is a prodrug that has been widely used in the treatment of advanced cancers and is activated by human carboxylesterase 2. Although its gene presents several polymorphisms and an intronic SNP is found to be associated with reduced carboxylesterase 2 mRNA expression in colorectal tumor , none of the variations in the carboxylesterase 2 gene are found to be associated with protein activity (Charasson et al 2004). Similarly, the polymorphism in the histamine-N-methyltransferase gene is not associated with gastric ulcer ).…”

Section: Genomic Variation and Drug Metabolizing Genesmentioning

confidence: 99%

Genetic diversity and new therapeutic concepts

Shastry

2005

J Hum Genet

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The differences in medicinal drug responses among individuals had been known for quite some time. Some patients exhibit a life-threatening adverse reaction while others fail to show an expected therapeutic effect. Intermediate responses between the above two extreme cases are also known. In fact, it has been recently reported that approximately 100,000 deaths and more than 2 million hospitalizations annually in the United States are due to properly prescribed medications. This interindividual variability could be due in part to genetically determined characteristics of target genes or drug metabolizing enzymes. This has now been substantiated by a variety of studies. We know that ''one size fits all'' is not correct. Therefore, the application of pharmacogenetic concepts to clinical practice is an excellent goal in the postgenomic era. The successful completion of the human genome project provided necessary molecular tools, such as high-throughput SNP genotyping, HapMap, and microarray, that can be applied to develop proper therapeutic options for individuals. Recently, there have been considerable scientific, corporate, and policy interest in pharmacotherapy. However, identification of causal variations in a target gene is only a starting point, and the progress in this rapidly developing field is slower than expected. One major drawback could be due to the multigene determinant of drug response that requires a genome-wide screening. Additionally, application of pharmacogenetic knowledge into clinical practice requires a high level of accuracy, precision (risk/benefit ratio), and strict regulations. This is because the pharmacogenetic approach raises several ethical, moral, and legal questions. It is also necessary that both health professionals and the general public must be urgently educated. Despite these limitations, translation of pharmacogenomic data into clinical practice would certainly provide better opportunities to increase the safety and efficacy of medicine in the future.

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Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN-38

Abstract: The hCE2 gene presents several polymorphisms, none of which seems to be involved in significant variations in protein activity and, therefore, in irinotecan activation.

Cited by 66 publications

References 17 publications

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

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

Haplotypes and a Novel Defective Allele of CES2 Found in a Japanese Population

Genetic diversity and new therapeutic concepts

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