p450 - publications

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1. Clin Pharmacol Ther. 2012 Apr 18. doi: 10.1038/clpt.2011.336. [Epub ahead of

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

Klein K, Thomas M, Winter S, Nussler AK, Niemi M, Schwab M, Zanger UM.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart,

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.

PMID: 22510778 [PubMed - as supplied by publisher]