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Histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in HepG2 cells

Title
Histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in HepG2 cells
Authors
Kim, JYAhn, MRKim, DKSheen, YY
Ewha Authors
신윤용김대기
SCOPUS Author ID
신윤용scopus; 김대기scopus
Issue Date
2004
Journal Title
ARCHIVES OF PHARMACAL RESEARCH
ISSN
0253-6269JCR Link
Citation
vol. 27, no. 4, pp. 407 - 414
Keywords
CYP3A4PCNrifampicinRU486SXRHDACIN2001HepG2d
Publisher
PHARMACEUTICAL SOCIETY KOREA
Indexed
SCIE; SCOPUS; KCI WOS scopus
Abstract
The expression of CYP3A4 gene is induced by a variety of structurally unrelated xenobiotics including the antibiotic rifampicin, pregnenolone 16-carbonitrile (PCN), and endogenous hormones, that might mediate through steroid and xenobiotic receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. In order to gain the insight of the molecular mechanism of CYP3A4 gene expression, study has been undertaken to investigate if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter in human hepatoma HepG2 cells. Also we have investigated to see if SXR is involved in the regulation of CYP3A4 proximal promoter activity in human hepatoma HepG2 cells. HepG2 cells were transfected with a plasmid pCYP3A4-Luc containingsimilar to1 kb of the CYP3A4 proximal promoter region (-863 to +64 bp) in front of a reporter gene, luciferase, in the presence or absence of pSAP-SXR. In HepG2 cells, CYP3A4 inducers, such as rifampicin, PCN and RU486 showed minimal stimulation of CYP3A4 proximal promoter activity in the absence of SXR and histone deacetylase (HIDAC) inhibitors. 4-Dimethylamino-N-[4-(2-hydroxycarbamoylvinyl)benzyl]benzamide (IN2001), a new class HDAC inhibitor significantly increased CYP3A4 proximal promoter activity over untreated control cells and rifampicin concomitant treatment with IN2001 increased further CYP3A4 proximal promoter activity that was stimulated by IN2001. The results of this study demonstrated that both HDAC inhibitors and SXR are essential to increase of CYP3A4 proximal promoter activity by CYP3A4 inducers such as PCN, rifampicin, and RU486. Especially SXR seems to be important for the dose dependent response of CYP3A4 inducing chemicals to stimulate CYP3A4 proximal promoter activity. Also this data suggested that HDAC inhibitors seemed to facilitate the CYP3A4 proximal promoter to be activated by chemicals.
DOI
10.1007/BF02980082
Appears in Collections:
약학대학 > 약학과 > Journal papers
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