Baker_2015_J.Biochem.Mol.Toxicol_29_545

Nuclear receptors and transcription factors regulate the mRNA expression of many drug metabolizing enzymes, including the carboxylesterases (Ces). However, there are few data regarding whether these changes in mRNA expression result in alteration of protein levels or activity. In the present study, we sought to determine the isoform-specific regulation of hepatic Ces mRNA expression and activity following the administration of pharmacological activators of the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and nuclear factor E2-related protein (Nrf2) to mice. The CAR activator 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and PXR ligand pregnenolone-16a-carbonitrile (PCN) increased Ces mRNA expression of various Ces2 isoforms, whereas the Nrf2 activator butylated hydroxyanisole primarily reduced Ces3a mRNA expression and induced Ces1g mRNA. TCPOBOP and PCN increased Ces2 hydrolytic activity in an isoform-specific manner. Taken together, these data demonstrate that activation of CAR, PXR, and Nrf2 regulates not only Ces mRNA expression, but also isoform-specific activity.