CARBOXYLESTERASES: PHARMACOLOGICAL INHIBITION REGULATED EXPRESSION AND TRANSCRIPTIONAL INVOLVEMENT OF NUCLEAR RECEPTORS AND OTHER TRANSCRIPTION FACTORS Yuanjun Shen1, Zhanquan Shi2 and Bingfang Yan2,3 Division of Pharmaceutical Sciences James L. Winkle College of Pharmacy University of Cincinnati Cincinnati, OH 45229 USA. Address Correspondence to: Dr. Bingfang Yan Division of Pharmaceutical Sciences James L. Winkle College of Pharmacy University of Cincinnati Cincinnati, OH 45229 Phone: (513) 558-6297 Fax: (513) 558-3233 E-mail:
[email protected] Running Title: Regulated expression and inhibited activity of carboxylesterases FOOTNOTES 1 Current address: Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh Department of Medicine, Pittsburgh, PA 15261, USA. 2 Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45229, USA 3 To whom correspondence should be addressed. 4 This work was supported by National Institutes of Health Grants R01GM61988 and R01EB018748. 5 Abbreviation used: CAR, Constitutive androstane receptor; CES1, carboxylesterase-1; DEC1, Differentiated embryo chondrocyte-1; 5-FU: Fluorouracil; GR, Glucocorticoid receptor; IL-6, Interlekin- 6; LPS, Lipopolysaccharides; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; p53, Tumor protein p53; PXR, Pregnane X receptor Carboxylesterases (CESs, E.C.3.1.1.1) constitute a large class of enzymes that determine the therapeutic efficacy and toxicity of ester/amide drugs. Without exceptions, all mammalian species studied express multiple forms of carboxylesterases. Two human carboxylesterases, CES1 and CES2, are major contributors to hydrolytic biotransformation. Recent studies have identified therapeutic agents that potently inhibit carboxylesterases-based catalysis. Some of them are reversible whereas others irreversible. The adrenergic antagonist carvedilol, for example, reversibly inhibits CES2 but this carboxylesterase is irreversibly inhibited by orlistat, a popular anti-obesity medicine.