Suppression of carboxylesterases by imatinib mediated by the down-regulation of pregnane X receptor.

BACKGROUND AND PURPOSE: Imatinib mesylate (IM) is a first-line treatment for chronic myeloid leukaemia (CML) as a specific inhibitor of BCR-ABL tyrosine kinase. As IM is widely used in CML, in combination with other drugs, the effects of IM on drug-metabolizing enzymes (DMEs) are crucial to the design of rational drug administration. Carboxylesterases (CESs) are enzymes catalysing the hydrolytic biotransformation of several clinically useful drugs. Although IM is known to inhibit cytochromes P450 (CYPs), its effects on DMEs, and CESs in particular, are still largely undefined.

EXPERIMENTAL APPROACH: Hepatoma cell lines (HepG2 and Huh7) and primary mouse hepatocytes were used. mRNA and protein expression were evaluated by quantitative RT-PCR and Western blot analysis. Reporter luciferase activity was determined by transient co-transfection experiment. Pregnane X receptor (PXR) expression was regulated by overexpression and RNA interference. The activity of CESs was determined by enzymic and toxicological assays. Mice were treated with a range of doses of IM to analyse expression of CESs in mouse liver.

KEY RESULTS: The expression and activity of CESs were markedly repressed by IM, along with the down-regulation of PXR and inhibited expression and activity of CYP3A4 and P-gp.

CONCLUSIONS AND IMPLICATIONS: Down-regulation of PXR mediates IM-induced suppression of CESs. IM may inhibit expression of other genes targeted by PXR, thus inducing a wide range of potential drug-drug interactions during treatment of CML. The data deserve further elucidation including clinical trials.