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Trichostatin A, a histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in hepa-l cells

Title
Trichostatin A, a histone deacetylase inhibitor stimulate CYP3A4 proximal promoter activity in hepa-l cells
Authors
Ahn, 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. 415 - 421
Keywords
CYP3A4PCNrifampicinRU486SXRHDACIN2002hepa I
Publisher
PHARMACEUTICAL SOCIETY KOREA
Indexed
SCIE; SCOPUS; KCI WOS scopus
Abstract
Cytochrome P450 3A4 (CYP3A4) is the most abundant CYPs in human liver, comprising approximately 30% of the total liver CYPs contents and is involved in the metabolism of more than 60% of currently used therapeutic drugs. However, the molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. Thus, this study has been carried out to gain the insight of the molecular mechanism of CYP3A4 gene expression, investigating if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter. Also SXR was investigated to see if they were involved in the regulation of CYP3A4 proximal promoter activity. Hepa-I cells were transfected with a plasmid containing similar to1 kb of the human CYP3A4 proximal promoter region (863 to +64 bp) cloned in front of a reporter gene, luciferase, in the presence or absence of SXR. Transfected cells were treated with CYP3A4 inducers such as rifampicin, PCN and RU 486, in order to examine the regulation of CYP3A4 gene expression in the presence or absence of trichostatin A (TSA). In Hepa-l cells, CYP3A4 inducers increased modestly the luciferase activity when TSA was co-treated, but this increment was not enhanced by SXR cotransfection. Taken together, these results indicated that the inhibition of histone deacetylation was required to SXR-mediated increase in CYP3A4 proximal promoter region when rifampicin, or PCN was treated. Further a trans-activation by SXR may demand other species-specific transcription factors.
DOI
10.1007/BF02980083
Appears in Collections:
약학대학 > 약학과 > Journal papers
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