title: Suppression of carboxylesterases by imatinib mediated by the down-regulation of pregnane X receptor.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.|Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.|Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Department of Pharmacy, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Clinical Pharmacology Laboratory, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Liu
authors.affiliation: Clinical Pharmacology Laboratory, Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Fan
authors.affiliation: Research Center of Biotechnology, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Xi
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Jing
authors.identifier: 0000-0002-9712-6771
authors.initials: J
authors.lastname: Xiong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid / Q000096:biosynthesis* / Q000172:deficiency* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D000068877:Imatinib Mesylate; D002265:Carboxylic Ester Hydrolases