Dexamethasone transcriptionally increases the expression of the pregnane X receptor and synergistically enhances pyrethroid esfenvalerate in the induction of cytochrome P450 3A23

被引：32

作者：

Shi, Deshi ^{[1
]}

Yang, Dongfang ^{[1
]}

Yan, Bingfang ^{[1
]}

机构：

[1] Univ Rhode Isl, Dept Biomed Sci, Ctr Pharmacogenom & Mol Therapy, Kingston, RI 02881 USA

来源：

BIOCHEMICAL PHARMACOLOGY | 2010年 / 80卷 / 08期

关键词：

Pregnane X receptor; Transactivation; CYP3A23; Esfenvalerate; Dexamethasone; GLUCOCORTICOID RESPONSE ELEMENT; HUMAN HEPATOCYTES; IN-VITRO; TARGET GENES; PXR; CYP3A4; PROTEIN; RAT; DELTAMETHRIN; METABOLISM;

D O I：

10.1016/j.bcp.2010.06.043

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The pregnane X receptor (PXR) is recognized as a key regulator for the induction of a large number of genes in drug metabolism and transport. The transactivation of PXR is enhanced by the glucocorticoid dexamethasone and the enhancement is linked to the induction of PXR in humans and rats. The present study was undertaken to determine the mechanism for the induction and ascertain the synergistic effect on the expression of CYP3A23, a rat PXR target. In primary hepatocytes, significant induction of PXR was detected as early as 2 h after the treatment and the maximal induction occurred at 1 mu M dexamethasone. Similar induction kinetics was observed in the hepatoma line H4-II-E-C3. The induction was abolished by actinomycin D and dexamethasone efficaciously stimulated the rat PXR promoter. In addition, dexamethasone synergized esfenvalerate (an insecticide and a PXR activator) in inducing CYP3A23 and stimulating the CYP3A23 promoter. The full promoter of CYP3A23 (-1445/+74) was activated in a similar pattern as the changes in PXR mRNA in response to dexamethasone, esfenvalerate and co-treatment. In contrast, different responding patterns were detected on the stimulation of the CYP3A23 proximal promoter. Synergistic stimulation was also observed on the CYP3A4-DP-Luc reporter, the human counterpart of CYP3A23. These findings establish that transactivation is responsible for the induction of rat PXR and the induction presents potential interactions with insecticides in a species-conserved manner. The different responding patterns among CYP3A23 reporters point to an involvement of multiple transcriptional events in the regulation of CYP3A23 expression by dexamethasone, esfenvalerate and both. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：1274 / 1283

页数：10

共 46 条

[11] Glucocorticoid-mediated induction of CYP3A4 is decreased by disruption of a protein: DNA interaction distinct from the pregnane X receptor response element [J].

El-Sankary, W ;

Bombail, V ;

Gibson, GG ;

Plant, N .

DRUG METABOLISM AND DISPOSITION, 2002, 30 (09) :1029-1034

[12] The role of enzyme induction and inhibition on cypermethrin hepatotoxicity [J].

El-Tawil, OS ;

Abdel-Rahman, MS .

PHARMACOLOGICAL RESEARCH, 2001, 44 (01) :33-39

[13]

Gerbal-Chaloin S, 2001, DRUG METAB DISPOS, V29, P242

[14] Identification of rat and human cytochrome P450 isoforms and a rat serum esterase that metabolize the pyrethroid insecticides deltamethrin and esfenvalerate [J].

Godin, Stephen J. ;

Crow, J. Allen ;

Scollon, Edward J. ;

Hughes, Michael F. ;

DeVito, Michael J. ;

Ross, Matthew K. .

DRUG METABOLISM AND DISPOSITION, 2007, 35 (09) :1664-1671

[15] Species differences in the in vitro metabolism of deltamethrin and esfenvalerate: Differential oxidative and hydrolytic metabolism by humans and rats [J].

Godin, Stephen J. ;

Scollon, Edward J. ;

Hughes, Michael F. ;

Potter, Philip M. ;

DeVito, Michael J. ;

Ross, Matthew K. .

DRUG METABOLISM AND DISPOSITION, 2006, 34 (10) :1764-1771

[16] Glucocorticoid receptor β in acute and chronic inflammatory conditions:: Clinical implications [J].

Goecke, A ;

Guerrero, J .

IMMUNOBIOLOGY, 2006, 211 (1-2) :85-96

[17] Regulation of CYP3A gene transcription by the pregnane X receptor [J].

Goodwin, B ;

Redinbo, MR ;

Kliewer, SA .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2002, 42 :1-+

[18] Two-stage glucocorticoid induction of CYP3A23 through both the glucocorticoid and pregnane X receptors [J].

Huss, JM ;

Kasper, CB .

MOLECULAR PHARMACOLOGY, 2000, 58 (01) :48-57

[19]

Kliewer SA, 2002, J LIPID RES, V43, P359

[20] Dual Mechanisms of CYP3A Protein Regulation by Proinflammatory Cytokine Stimulation in Primary Hepatocyte Cultures [J].

Lee, Choon-Myung ;

Pohl, Jan ;

Morgan, Edward T. .

DRUG METABOLISM AND DISPOSITION, 2009, 37 (04) :865-872

← 1 2 3 4 5 →