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Hypolipemiant effects on CYP3A4 and CYP3A5 mRNA expression in vitro and in vivo

Grant number: 07/02944-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): October 01, 2007
Effective date (End): September 30, 2011
Field of knowledge:Health Sciences - Pharmacy
Principal researcher:Rosario Dominguez Crespo Hirata
Grantee:Maria Alice Vieira Willrich
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

CYP3A4 and CYP3A5 are cytochrome P450 enzymes responsible for the biotransformation of endogenous steroids and xenobiotics. Statins are HMG-CoA reductase inhibitors used in the treatment of the hypercholesterolemia. Single nucleotide polymorphisms (SNPs) in CYP3A4 and CYP3A5 genes (CYP3A4*1B and CY3A5*3C) had been associated with differences in the hipolipemiant response of individuals treated with atorvastatin. Moreover, for CYP3A5, it was found there is an association of the SNP with decreased expression of mRNA. The regulation mechanisms of gene expression for CYP3A4 and CYP3A5 mediated by statins are not completely known. It is possible that regulation of the expression is modulated by nuclear receptors such as PXR, that activates the transcription of one of the involved genes in drug biotransformation. Lovastatin was pointed as a ligand of this transcription factor, and it is very possible that atorvastatin acts in the same way. In this study, atorvastatin effects on the expression and the functional activity of CYP3A4 and CYP3A5 in HepG2 and Caco-2 cell lines and in human lymphocytes will be evaluated. Total RNA and proteins will be extracted of cells in culture. The stability of CYP3A4 and CYP3A5 mRNA will be analyzed by Northern Blotting. The expression of CYP3A4 and CYP3A5 mRNA will be evaluated by Real Time PCR. Protein expression will be detected by Western Blot and flow citometry. The functional activity of CYP3A4 and CYP3A5 in the cells will be evaluated by HPLC, through the triazolam hydroxylation assay on atorvastatina treated and not treated HepG2 and Caco-2 cell lines. The possible link between gene expression, functional activity of enzymes and SNPs CYP3A4*1B and CYP3A5*3C will be analyzed. The effect of atorvastatin in the activation of the transcription factors such as PXR and RXR for CYP3A4 and CYP3A5 will be evaluated by EMSA. The results of this study will provide data about components and mechanisms involved in the variable response to hipolipemiant treatment with atorvastatin.

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Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
WILLRICH, Maria Alice Vieira. Hypolipemiant effects on CYP3A4 and CYP3A5 mRNA expression in vitro and in vivo. 2011. Doctoral Thesis - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.