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

Abstract

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.

Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977

“…Clone A cells are derived from Huh7 cells, a hepatoma cell line that is permissive for HCV replicon replication (26). The suppression of CES1 may be common in hepatoma cell lines; Yang et al (27) have previously reported that HepG2 cells, another hepatoma cell line, expressed much lower levels of CES1 than primary hepatocytes. Telaprevir, which was found to be an inhibitor of CatA, inhibited the metabolism of PSI-7851 in clone A.…”

Carboxylesterases: structure, function and polymorphism in mammals

“…It includes human intestinal CE (CES2A1), 34,[40][41][42][43][44] rat CES2 (CES2A10), 22) rat intestinal CE RL4 (rCES2) (CES2A6), 45) rabbit form 2 46) and hamster AT51 (CES2A11). 47) CES3 includes ES-male (CES3A2) and human CES3 (CES3A1).…”

Carboxylesterases: Structure, Function and Polymorphism

“…It includes human intestinal CarbE (CES2A1) (Schwer et al, 1997;Humerickhouse et al, 2000;Imai et al, 2006;Taketani et al, 2007;Yang et al, 2007;Shi et al, 2008), rCES2 (CES2A10) (Furihata et al, 2005), rat intestinal CarbE RL4 (rCES2) (CES2A6) (Furihata et al, 2003), rabbit form 2 (Ozols, 1989) and hamster AT51 (CES2A11) (Sone et al, 1994). CES3 includes ES-male (CES3A2) and human CES3 (CES3A1) (Aida et al, 1993;Sanghani et al, 2004).…”