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Dexamethasone regulates differential expression of carboxylesterase 1 and carboxylesterase 2 through activation of nuclear receptors

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Summary

Carboxylesterases (CESs) play important roles in the metabolism of endogenous and foreign compounds in physiological and pharmacological responses. The aim of this study was to investigate the effect of dexamethasone at different doses on the expression of CES1 and CES2. Imidapril and irinotecan hydrochloride (CPT-11) were used as special substrates for CES1 and CES2, respectively. Rat hepatocytes were cultured and treated with different concentrations of dexamethasone. The hydrolytic activity of CES1 and CES2 was tested by incubation experiment and their expression was quantitated by real-time PCR. A pharmacokinetic study was conducted in SD rats to further evaluate the effect of dexamethasone on CESs activity in vivo. Western blotting was performed to investigate the regulatory mechanism related to pregnane X receptor (PXR) and glucocorticoid receptor (GR). The results showed that exposure of cultured rat hepatocytes to nanomolar dexamethasone inhibited the imidapril hydrolase activity, which was slightly elevated by micromolar dexamethasone. For CES2, CPT-11 hydrolase activity was induced only when dexamethasone reached micromolar levels. The real-time PCR demonstrated that CES1 mRNA was markedly decreased by nanomolar dexamethasone and increased by micromolar dexamethasone, whereas CES2 mRNA was significantly increased by micromolar dexamethasone. The results of a complementary animal study showed that the concurrent administration of dexamethasone significantly increased the plasma concentration of the metabolite of imidapril while the ratio of CPT-11 to its metabolite SN-38 was significantly decreased. PXR protein was gradually increased by serial concentrations of dexamethasone. However, only nanomolar dexamethasone elevated the level of GR protein. The different concentrations of dexamethasone required suggested that suppression of CES1 may be mediated by GR whereas the induction of CES2 may result from the role of PXR. It was concluded that dexamethasone at different concentrations can differentially regulate CES1 and CES2.

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Authors and Affiliations

  1. Department of Pharmacy, Huazhong University of Science and Technology, Wuhan, 430030, China

    Chengliang Zhang  (张程亮), Ping Gao  (高 萍), Yanjiao Xu  (徐艳娇), Daochun Xiang  (向道春) & Dong Liu  (刘 东)

  2. Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Weifeng Yin  (印卫峰)

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  1. Chengliang Zhang  (张程亮)
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  2. Ping Gao  (高 萍)
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  3. Weifeng Yin  (印卫峰)
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  4. Yanjiao Xu  (徐艳娇)
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  5. Daochun Xiang  (向道春)
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  6. Dong Liu  (刘 东)
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Correspondence to Dong Liu  (刘 东).

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The authors contributed equally to this work.

This project was supported by a grant from the Natural Science Foundation of Hubei Province of China (No. 2011CDB550).

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Zhang, C., Gao, P., Yin, W. et al. Dexamethasone regulates differential expression of carboxylesterase 1 and carboxylesterase 2 through activation of nuclear receptors. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 32, 798–805 (2012). https://doi.org/10.1007/s11596-012-1037-z

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  • DOI: https://doi.org/10.1007/s11596-012-1037-z

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