title: 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.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.forename: Maria
authors.initials: M
authors.lastname: Thomas
authors.forename: Stefan
authors.initials: S
authors.lastname: Winter
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nussler
authors.forename: Mikko
authors.initials: M
authors.lastname: Niemi
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Ulrich M
authors.initials: UM
authors.lastname: Zanger
mesh_terms: D000924:Anticholesteremic Agents / Q000378:metabolism; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D000069059:Atorvastatin; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003627:Data Interpretation, Statistical; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics* / Q000502:physiology*; D005838:Genotype; D022781:Hepatocytes / Q000378:metabolism; D006538:Heptanoic Acids / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011758:Pyrroles / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D047493:PPAR alpha; D011758:Pyrroles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000069059:Atorvastatin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human