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 singlenucleotide 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.

Modelling of atorvastatin pharmacokinetics and the identification of the effect of a BCRP polymorphism in the Japanese population

“…It can be hypothesised that the lack of effect in the current work may be due to the small sample size and the complete absence of homozygous variant individuals with respect to these SNPs (Table 2). Similarly, the effects of two other SNPs that have been of particular clinical interest recently, namely rs35599367 (CYP3A4) and rs4253728 (PPARA) [18,23,26], were not possible to be investigated in the current work as all studied individuals carried the homozygous wild-type genotype (Table 2).…”

“…For the purpose of this work, all studied participants were retrospectively genotyped for 18 genetic polymorphisms located in 7 different genes. More specifically 3, 3, 1, 1, 7, 2 and 1 polymorphisms were genotyped in the ABCB1, ABCG2, CYP3A4, CYP3A5, SLCO1B1, SLCO2B1 and PPARA genes respectively, as previous literature suggests that all these genes might be implicated in atorvastatin disposition [14,15,[22][23][24][25][26]. The distribution of these variants in the studied population is reported in Table 2.…”

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

“…These results are in concordance with the reduced CYP3A4 protein/activity levels previously observed in vitro. [54] At present, PPARA c.208+3819A>G appears to be the PPARA sequence variant with the strongest influence on Tac pharmacokinetics but this observation requires confirmation.…”

“…In vitro, PPARA c.209-1003G>A and c.208+3819A>G were associated with reduced expression of PPAR-α, and consistently related to lower CYP3A4 mRNA levels, protein expression, and enzymatic activity. [54] Recently, Lunde et al found that expression of at least one PPARA variant allele was significantly associated with a higher Tac C 0 /D ratio, when adjusting for POR*28, CYP3A5*3, and CYP3A4*22 among 229 kidney transplant recipients. [48] A detailed analysis of the two PPARA sequence variants showed significantly increased Tac exposure in patients homozygous for PPARA-α c.209-1003G>A.…”

Role of Chromatin Structural Changes in Regulating Human CYP3A Ontogeny

“…Adding to uncertainty, the length of this hypervariable period varies from one enzyme to another (Hines, 2008). Although these hypervariable windows likely are linked to variability in the molecular mechanisms controlling enzyme ontogeny (Schuetz, 2004;Perera et al, 2009;Klein et al, 2012), those regulatory mechanisms remain largely unknown.…”