Dexamethasone suppresses the expression of multiple rat carboxylesterases through transcriptional repression: Evidence for an involvement of the glucocorticoid receptor

Abstract

Carboxylesterases play important roles in the metabolism of xenobiotics and detoxication of insecticides. Without exception, all mammalian species studied express multiple forms of carboxylesterases. Several rat carboxylesterases are well-characterized including hydrolase A, B and S, and the expression of these enzymes is significantly suppressed by glucocorticoid dexamethasone. In this study, we used multiple experimental systems and presented a molecular mechanism for the suppression. Rats receiving one or more daily injections of dexamethasone consistently expressed lower HA, HB and HS. The suppression occurred at the levels of mRNA, protein and hydrolytic activity. In hepatoma cell line H4-II-E-C3, nanomolar dexamethasone caused significant decreases in HA, HB and HS mRNA, and the decreases were abolished by antiglucocorticoid RU486. Additionally, dexamethasone at nanomolar concentrations repressed the promoters of carboxylesterases, and the repression was reduced by glucocorticoid receptor-β, a dominant negative regulator of the glucocorticoid receptor (GR). In contrast, co-transfection of the pregnane X receptor (PXR) increased the reporter activities, but the increase occurred only at micromolar concentrations of dexamethasone. These findings establish that both GR and PXR are involved in the regulated expression of rat carboxylesterases by dexamethasone but their involvement depends on the concentrations.

Transcription Factor-Mediated Regulation of Carboxylesterase Enzymes in Livers of Mice

“…Both PXR and GR were shown to be activated by DEX (Shi et al, 2008). Activation of PXR requires micromolar concentrations of DEX, whereas activation of GR requires nanomolar concentrations.…”

“…In the present study, DEX suppressed almost all of the Ces1 isozymes, as well as Ces3a, in livers of mice. Both PXR and GR are known to mediate DEX regulation of rat Cess, and the concentration of DEX determines the involvement of PXR and/or GR in the suppression of rat Ces1d and Ces1f (Shi et al, 2008). To determine the role of PXR in DEX suppression of mouse Cess, both a low dose (2 mg/kg) and a high dose (50 mg/kg) of DEX were administered to WT and PXR-null mice.…”

Carboxylesterases: structure, function and polymorphism in mammals

“…It includes human intestinal CE (CES2A1), 34,[40][41][42][43][44] rat CES2 (CES2A10), 22) rat intestinal CE RL4 (rCES2) (CES2A6), 45) rabbit form 2 46) and hamster AT51 (CES2A11). 47) CES3 includes ES-male (CES3A2) and human CES3 (CES3A1).…”

Distinct Patterns of Aging Effects on the Expression and Activity of Carboxylesterases in Rat Liver and Intestine

“…For example, phenobarbital moderately induces Hydrolase A and Hydrolase B in rat liver (Morgan et al, 1994). In contrast, dexamethasone suppresses Hydrolase A, Hydrolase B, and Hydrolase S (also known as ES-1, a plasma CES1 isozyme; Shi et al, 2008), while it induces RL4 (Furihata et al, 2005).…”