FUNCTIONAL CHARACTERIZATION OF THREE NATURALLY OCCURRING SINGLE NUCLEOTIDE POLYMORPHISMS IN THE<i>CES2</i>GENE ENCODING CARBOXYLESTERASE 2 (HCE-2)

Kubo, Takashi; Kim, Su-Ryang; Sai, Kimie; Saito, Yoshiro; Nakajima, Toshiharu; Matsumoto, Kenji; Saito, Hirohisa; Shirao, Kuniaki; Yamamoto, Noboru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Ohno, Yasuo; Ozawa, Shogo; Sawada, Jun‐ichi

doi:10.1124/dmd.105.005587

Cited by 48 publications

(46 citation statements)

References 21 publications

(25 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…45 Several CES2 variants have been shown to be functionally deficient, and some have decreased esterase activities toward the anticancer agent irinotecan. 46 CES are clearly important in a variety of pharmacogenetic phenotypes. No studies to date, however, have addressed CES genes in drug-induced hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

et al. 2010

View full text Add to dashboard Cite

Treatment of latent tuberculosis infection (LTBI) generally includes isoniazid (INH), a drug that can cause serious hepatotoxicity. Carboxylesterases (CES) are important in the metabolism of a variety of substrates, including xenobiotics. We hypothesized that genetic variation in CES genes expressed in the liver could affect INH-induced hepatotoxicity. Three CES genes are known to be expressed in human liver: CES1, CES2 and CES4. Our aim was to systematically characterize genetic variation in these novel candidate genes and test whether it is associated with this adverse drug reaction. As part of a pilot study, 170 subjects with LTBI who received only INH were recruited, including 23 cases with hepatotoxicity and 147 controls. All exons and the promoters of CES1, CES2 and CES4 were bidirectionally sequenced. A large polymorphic deletion was found to encompass exons 2 to 6 of CES4. No significant association was found. Eleven single-nucleotide polymorphisms (SNPs) in CES1 were in high linkage disequilibrium with each other. One of these SNPs, C(À2)G, alters the translation initiation sequence of CES1 and represents a candidate functional polymorphism. Replication of this possible association in a larger sample set and functional studies will be necessary to determine if this CES1 variant has a role in INH-induced hepatotoxicity.

show abstract

Section: Discussionmentioning

confidence: 99%

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

et al. 2010

View full text Add to dashboard Cite

show abstract

Section: Methodsmentioning

confidence: 99%

“…The SNP 1AϾT is nonsynonymous (M1L) and results in a substitution of the translation initiation codon ATG to TTG in the CES2 gene. The other novel SNPs were located in the introns or the 5Ј-flanking region.The nonsynonymous SNP 424GϾA (V142M) reported by our group (Kubo et al, 2005) and another nonsynonymous SNP 617GϾA (R206H) published in the dbSNP (rs8192924) and JSNP (ssj0005417) databases were found at a frequency of 0.002. Recently, several noncoding SNPs in CES2 were also reported (Kim et al, 2003;Charasson et al, 2004;Marsh et al, 2004;Wu et al, 2004).…”

mentioning

confidence: 99%

“…The sequence of the variant cDNA was confirmed in both strands, and the resultant plasmid was designated pcDNA3.1/CES2L-A1T. Expression plasmids for the short-form wild-type (CES2S) and Arg 206 His variant CES2 were prepared and introduced into COS-1 cells according to the method described previously (Kubo et al, 2005).Expression of Wild-Type and Variant CES2 Proteins in COS-1 Cells. Expression of wild-type and variant CES2 proteins in COS-1 cells was examined as described previously (Kubo et al, 2005).…”

mentioning

confidence: 99%

“…Expression plasmids for the short-form wild-type (CES2S) and Arg 206 His variant CES2 were prepared and introduced into COS-1 cells according to the method described previously (Kubo et al, 2005).…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Kim

Sai²,

Tanaka-Kagawa³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

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 ...

show abstract

Carboxylesterases

Yan¹

2012

Encyclopedia of Drug Metabolism and Interactions

View full text Add to dashboard Cite

Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that hydrolyze chemicals containing such a functional group as a carboxylic acid ester, amide, and thioester. These enzymes are major pharmacokinetic determinants of ester/amide drugs and detoxify against organophosphorus and pyrethroid insecticides. In addition, these enzymes hydrolyze endogenous lipids and involve the assembling of lipoproteins. CESs exhibit overlapping substrate specificity; however, many drugs are hydrolyzed predominately by a single CES. Although there are exceptions, the relative sizes between the alcohol and acyl (acid) moieties of an ester contribute significantly to the isoform‐specific hydrolysis. CES activity is widely distributed in mammalian tissues, with the highest level in liver microsomes. High abundance of CESs in the liver is linked to certain cellular roles, notably in directing protein trafficking. CESs belong to the superfamily of α/β fold proteins and have similar crystal structure to other enzymes in this superfamily. CESs use a two‐step mechanism for catalysis. Hydrolysis of carboxylic acid esters leads to the formation of an alcohol and a carboxylic acid. Compounds with these moieties are substrates for conjugation enzymes or transporters. Likewise, hydrolysis may create or eliminate a substrate of other phase I enzymes, particularly cytochrome P450s. Like many other drug‐metabolizing enzymes, the expression of CESs is regulated by many factors including age, hormones, therapeutic agents, and environmental chemicals. Mammalian species express multiple forms of CESs. However, there are notable differences in substrate specificity, tissue distribution, and regulated expression.

show abstract

FUNCTIONAL CHARACTERIZATION OF THREE NATURALLY OCCURRING SINGLE NUCLEOTIDE POLYMORPHISMS IN THECES2GENE ENCODING CARBOXYLESTERASE 2 (HCE-2)

Abstract: ABSTRACT:Twelve single nucleotide polymorphisms (SNPs) in the human CES2 gene, which encodes a carboxylesterase, hCE-2 [human carboxylesterase 2 (EC 3.1.

Cited by 48 publications

References 21 publications

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

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

Carboxylesterases

Contact Info

Product

Resources

About