Glucose dominates the regulation of carboxylesterases induced by lipopolysaccharide or interleukin-6 in primary mouse hepatocytes

Abstract

Aims: Altered drug disposition has been associated with inflammation and diabetes, leading to the alteration of drug efficacy and toxicity. Carboxylesterases are major hydrolytic enzymes in the liver, catalyzing the hydrolytic biotransformation of numerous therapeutic agents. Therefore, how glucose affects the regulation of carboxylesterases by interleukin-6 (IL-6) and lipopolysaccharide (LPS) were investigated. Main methods: Primary mouse hepatocytes were cultured. Protein levels were measured by Western blot or enzyme linked immunosorbent assay (ELISA), while confocal laser scanning microscope and flow cytometry were used to confirm the activation of pregnane X receptor (PXR). Carboxylesterase activity was evaluated by enzymatic and toxicological assays. Key findings: Elevated glucose (11 or 25 mM) significantly increased carboxylesterase expression compared to 5.6 mM glucose. Carboxylesterase expression and activity were inhibited by LPS or IL-6 in 25 mM glucose, but stimulated in 5.6 mM glucose. The altered expression of carboxylesterases was not consistent with the activation of nuclear factor kappa B (NFκB) but repeatedly with the expression and activation of pregnane X receptor (PXR). The altered activation of PXR was further evidenced by the differential subcellular translocation and the expression of its target gene multidrug resistance 1 (MDR1). It implies that PXR, instead of inflammatory signaling, mediates the regulation of carboxylesterases by inflammatory mediators in different glucose concentrations. Significance: The findings contribute to clarify the regulation of carboxylesterases by inflammatory mediators, and indicate that carboxylesterase-involved drug metabolism and drug-drug interactions in diabetes should be reevaluated according to the intensity of inflammatory reactions and hyperglycemia.