Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK–NF-κB pathway

Abstract

Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as carboxylic acid ester, amide, and thioester. Hydrolysis of many drugs is reduced in liver diseases such as hepatitis and cirrhosis. In this study, we have demonstrated, in vitro and in vivo, treatment with LPS decreased the expression of HCE1 and HCE2 and the capacity of hydrolytic activity. In HepG2 cells, the decreased expression by LPS occurred at both mRNA and protein levels. Both HCE1 and HCE2 promoters were significantly repressed by LPS, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting the transrepression is responsible for suppressed expression. Further study showed that both PDTC, a NF-κB inhibitor, and SB203580, a p38MAPK inhibitor, could abolish the repression of HCE1 and HCE2 mediated by LPS, but U0126, a selective ERK1/2 inhibitor, could not do so, suggesting the repression of HCE1 and HCE2 by LPS through the p38MAPK-NF-κB pathway. In addition, being pretreated with LPS, HepG2 cells altered the cellular responsiveness to ester therapeutic agents, including clopidogrel (hydrolyzed by HCE1) and irinotecan (hydrolyzed by HCE2). The altered cellular responsiveness occurred at low micromolar concentrations, suggesting that suppressed expression of carboxylesterases by LPS has profound pharmacological and toxicological consequences, particularly with those that are hydrolyzed in an isoform-specific manner. This study provides new insight into the understanding of the pharmacological and toxicological effects and the mechanisms for repressing drug metabolism enzymes in inflammation.

Expression of proteins associated with adipocyte lipolysis was significantly changed in the adipose tissues of the obese spontaneously hypertensive/NDmcr-cp rat

“…CES3 is highly expressed in the liver, adipose tissue and also expressed in the small intestine, heart, and kidney [26]. The specific function of this enzyme has not yet been determined; however, it is speculated that carboxylesterases may play a role in lipid metabolism because endobiotics, such as triglyceride, cholesterol esters, and 2-arachidonoylglycerol are also substrates for carboxylesterases [27,28]. Given that carboxylesterases hydrolyzes long-chain fatty acid esters and thioesters, these enzymes have been considered therapeutic targets in the treatment of metabolic disorders, such as diabetes and atherosclerosis [29].…”

Aspafilioside B induces G2/M cell cycle arrest and apoptosis by up-regulating H-Ras and N-Ras via ERK and p38 MAPK signaling pathways in human hepatoma HepG2 cells

“…To investigate the effect of ROS inhibitor and MAPK inhibitors on aspafilioside B-induced cell cycle arrest, confluent cell culture were preincubated for 1 h with one of the following inhibitors before the addition of 12 mM aspafilioside B: 5 mM NAC, 5 mM SB203580 (p38 inhibitor), or 10 mM PD98059 (ERK inhibitor) [30,31].…”

Age-related inducibility of carboxylesterases by the antiepileptic agent phenobarbital and implications in drug metabolism and lipid accumulation

“…For example, interleukin-6, a proinflammatory cytokine, suppresses the expression of several human carboxylesterases [9]. Likewise, lipopolysaccharide, a potent proinflammatory stimulus, efficaciously down-regulates the expression of several mouse carboxylesterases [13]. Importantly, the suppressed expression by inflammatory mediators causes profound changes in cellular responsiveness to commonly used ester drugs.…”