Research Papers:

Impact of chronic unpredicted mild stress-induced depression on repaglinide fate via glucocorticoid signaling pathway

Hongyan Wei, Ting Zhou, Boyu Tan, Lei Zhang, Mingming Li, Zhijun Xiao and Feng Xu _

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Oncotarget. 2017; 8:44351-44365. https://doi.org/10.18632/oncotarget.17874

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Hongyan Wei1,2,*, Ting Zhou1,*, Boyu Tan2, Lei Zhang3, Mingming Li1, Zhijun Xiao1 and Feng Xu1,3

1Fengxian Hospital, Southern Medical University, Shanghai, China

2Hunan Provincial People’s Hospital, Hunan Normal University, Changsha, China

3Joint Research Center for Translation Medicine, East China Normal University, Shanghai, China

*These authors have contributed equally to this work

Correspondence to:

Feng Xu, email: [email protected]

Keywords: chronic unpredicted mild stress(CUMS), depression, repaglinide, drug-metabolizing enzymes (DMEs), glucocorticoid and adrenergic signaling pathway

Received: March 29, 2017     Accepted: April 24, 2017     Published: May 15, 2017


Chronic unpredicted mild stress (CUMS)-induced depression could alter the pharmacokinetics of many drugs in rats, however, the underlying mechanism is not clear. In this work we studied the pharmacokinetics of repaglinide, and explored the role of glucocorticoid and adrenergic signaling pathway in regulating drug metabolizing enzymes (DMEs) in GK rats and BRL 3A cells. The plasma cortisol and epinephrine levels were increased, meanwhile the pharmacokinetics of repaglinide were altered significantly in depression model rats. Forty-nine genes in liver of model rats displayed significant difference comparing to control rats. The differentially expressed genes enriched in the drug metabolism and steroid hormone biosynthesis pathway significantly, and Nr1i3 matched 335 connectivity genes. CAR and Ugt1a1 protein expression were enhanced significantly in liver of model rats. The mRNA expression of Ugt1a1 and Nr1i2 were increased 2 and 4 times respectively with dexamethasone (DEX) and 8-Br-cAMP co-treatment in BRL 3A cells. The protein expression of PXR was up-regulated, too. However, RU486 reversed the up-regulated effect. The adrenergic receptor agonists had little impact on the DMEs in BRL 3A. Our data suggested that CUMS-induced depression might up-regulate DMEs expression via glucocorticoid signaling pathway, and accelerate the fate of the repaglinide in spontaneous diabetes rats.

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