Received for publication April 5, 2007.
Revised May 29, 2007.
Accepted for publication May 30, 2007.

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 pro-inflammatory 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 carboxylesterases HCE1 and HCE2 by as much as 60%. The decreased expression occurred at both mRNA and protein levels and was confirmed by enzymatic assay. In co-transfection experiments, both HCE1 and HCE2 promoters were significantly repressed, and the repression was comparable as 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 anti-thrombogenic agent clopidogrel, whereas pretreatment with IL-6 increased it. 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.

Key words: Interleukins, Promoter analysis, Regulation of gene expression, Carboxylesterase, Antiviral drugs, Pharmacokinetics, metabolism and activation, Platelets