Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro

Tanimoto, Keiji; Kaneyasu, Mika; Shimokuni, Tatsushi; Hiyama, Keiko; Nishiyama, Masahiko

doi:10.1097/01.fpc.0000230110.18957.50

Cited by 37 publications

(39 citation statements)

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“…42 They are also involved in the metabolism of illegal drugs such as heroin and cocaine. 43 Genetic variants in both CES1 and CES2 genes may contribute to ADRs and increased 44 an angiotensin-converting enzyme inhibitor used to treat hypertension and congestive heart failure.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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“…In other words, an increase of systemic concentrations can indirectly lead to high oseltamivir concentrations in the CNS. In a previous report by Shi et al (27), several naturally occurring HCE1 polymorphic variants with different in vitro hydrolysis rates from the wild-type enzyme were described, and genetic variation in the HCE1 gene was also reported previously by other groups (3,28). The clinical relevance of these polymorphisms is unclear, and there are currently only sparse clinical data on the effect of genetic esterase polymorphisms on oseltamivir (and OC) pharmacokinetics in humans (30).…”

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confidence: 99%

Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System

Hoffmann¹,

Funk²,

Fowler³

et al. 2009

Antimicrob Agents Chemother

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Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.

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“…Based on the Human Genome sequence, HCE1 has two closely related genes, namely, HCE1A1 (AB119997) and HCE1A2 (AB119998). These two forms differ by four amino acids in the signaling peptide (Tanimoto et al, 2007). It is noteworthy that the expression of HCE1A2 but not HCE1A1 mRNA is correlated better with the sensitivity to anticancer drug irinotecan, although the precise mechanism for such a phenomenon remains to be determined (Tanimoto et al, 2007).…”

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confidence: 99%

“…These two forms differ by four amino acids in the signaling peptide (Tanimoto et al, 2007). It is noteworthy that the expression of HCE1A2 but not HCE1A1 mRNA is correlated better with the sensitivity to anticancer drug irinotecan, although the precise mechanism for such a phenomenon remains to be determined (Tanimoto et al, 2007). In addition, several sequences encoding HCE1 with one or more amino acid substitutions have been deposited into the GenBank, but they probably represent polymorphic variants of this carboxylesterase.…”

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confidence: 99%

Interleukin-6 Alters the Cellular Responsiveness to Clopidogrel, Irinotecan, and Oseltamivir by Suppressing the Expression of Carboxylesterases HCE1 and HCE2

Yang

Shi²,

Yang³

et al. 2007

Mol Pharmacol

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Carboxylesterases constitute a class of enzymes that play important roles in the hydrolytic metabolism of drugs and other xenobiotics. Patients with liver conditions such as cirrhosis show increased secretion of proinflammatory cytokines [e.g., interleukin-6 (IL-6)] and decreased capacity of hydrolysis. In this study, we provide a molecular explanation linking cytokine secretion directly to the decreased capacity of hydrolytic biotransformation. In both primary hepatocytes and HepG2 cells, treatment with IL-6 decreased the expression of human carboxyl-esterases HCE1 and HCE2 by as much as 60%. The decreased expression occurred at both mRNA and protein levels, and it was confirmed by enzymatic assay. In cotransfection experiments, both HCE1 and HCE2 promoters were significantly repressed, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting that transrepression is responsible for the suppressed expression. In addition, pretreatment with IL-6 altered the cellular responsiveness in an opposite manner of overexpression of HCE1 and HCE2 toward various ester therapeutic agents (e.g., clopidogrel). Transfection of HCE1, for example, decreased the cytotoxicity induced by antithrombogenic agent clopidogrel, whereas pretreatment with IL-6 increased the cytotoxicity. Such a reversal was observed with other ester drugs, including anticancer agent irinotecan and anti-influenza agent oseltamivir. The altered cellular responsiveness was observed when drugs were assayed at sub-and low-micromolar concentrations, suggesting that suppressed expression of carboxylesterases by IL-6 has profound pharmacological consequences, particularly with those that are hydrolyzed in an isoform-specific manner.

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Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro

Abstract: We demonstrated novel sequence structures and a functional role of CES1A genes in CPT-11 responses. We believe that our novel findings will be of key importance in developing a really useful prediction method for CPT-11 chemosensitivity.

Cited by 37 publications

References 10 publications

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

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

Nonclinical Pharmacokinetics of Oseltamivir and Oseltamivir Carboxylate in the Central Nervous System

Interleukin-6 Alters the Cellular Responsiveness to Clopidogrel, Irinotecan, and Oseltamivir by Suppressing the Expression of Carboxylesterases HCE1 and HCE2

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