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PPARA: A Novel Genetic Determinant of CYP3A4 In Vitro and In Vivo

Abstract:

Interindividual variability in cytochrome P450 3A4 (CYP3A4) is believed to be largely heritable; however, predictive genetic factors have remained scarce. Using a candidate-gene approach in a human liver bank, we identified single-nucleotide polymorphisms (SNPs) in the Ah-receptor nuclear translocator (ARNT), glucocorticoid receptor (GR), progesterone receptor membrane component 2 (PGRMC2), and peroxisome proliferator-activated receptor-α (PPARA) that are associated with CYP3A4 phenotype. Validation in atorvastatin-treated volunteers confirmed a decrease in atorvastatin-2-hydroxylation in carriers of PPARA SNP rs4253728. Homozygous carriers expressed significantly less PPAR-α protein in the liver. Moreover, shRNA-mediated PPARA gene knockdown in primary human hepatocytes decreased expression levels of the PPAR-α target ACOX1 and of CYP3A4 by more than 50%. In conclusion, this study identified novel genetic determinants of CYP3A4 that, together with nongenetic factors, explained 52, 55, and 33% of hepatic CYP3A4 mRNA, protein, and atorvastatin-2-hydroxylase activity, respectively. These findings have implications for variability in response to drug substrates of CYP3A4.

22510778

Projects: A3.4: Linking signalling to metabolic functions

Clinical pharmacology and therapeutics
Clin. Pharmacol. Ther. 91(6): 1044-52
18th Apr 2012

Kathrin Klein, Maria Thomas, Stefan Winter, Andreas K Nussler, Mikko Niemi, Matthias Schwab, Ulrich M Zanger

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[Kathrin Klein] [Maria Thomas] [Andreas Nüssler] [Matthias Schwab] [Ulrich Zanger]

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Views: 2816
  • Created: 14th May 2012 at 09:40
  • Last updated: 24th Oct 2013 at 16:16

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