Regulation of CYP3A4 and CYP2B6 expression by liver X receptor agonists

Abstract

The liver X receptor (LXR) agonists, 24(S),25-epoxycholesterol and T0901317, were previously shown to be capable of inducing CYP3A expression in primary cultured rodent hepatocytes through activation of the pregnane X receptor (PXR). In this study, the abilities of these two LXR agonists to regulate CYP3A4 and CYP2B6 mRNA expression in primary cultures of human hepatocytes were evaluated. Treatment with 10 or 30 microM of the endogenous oxysterol, 24(S),25-epoxycholesterol, had no effect on CYP3A4 mRNA content in five preparations of primary cultured human hepatocytes, while 30 microM 24(S),25-epoxycholesterol treatment increased CYP2B6 mRNA content by approximately two-fold. By comparison, treatment with the synthetic LXR agonist, T0901317, potently increased CYP3A4 and CYP2B6 mRNA levels in the human hepatocyte cultures, producing multi-fold increases at 10nM. Using a HepG2-based transactivation assay, T0901317 activated human PXR with an EC(50) approximately 20nM, which was more than 10-fold lower than that of the potent PXR ligand, SR-12813, while treatment with 24(S),25-epoxycholesterol failed to induce reporter expression in this assay. Therefore, while 24(S),25-epoxycholesterol-mediated PXR activation and CYP3A induction does not appear to be conserved from rodent to human, T0901317 is among the most potent known activators of human PXR.

Unveiling a New Essential Cis Element for the Transactivation of theCYP3A4Gene by Xenobiotics

“…8). These compounds were reported previously to activate the transcription of the CYP3A4 gene through hPXR (Bertilsson et al, 1998;Lehmann et al, 1998;Jones et al, 2000;Drocourt et al, 2001;Luo et al, 2002;Duniec-Dmuchowski et al, 2007;Matsubara et al, 2007). These findings further support the general function of eNR3A4 in hPXR-mediated CYP3A4 induction.…”

GW4064, an Agonist of Farnesoid X Receptor, Represses CYP3A4 Expression in Human Hepatocytes by Inducing Small Heterodimer Partner Expression

“…**P , 0.01; ***P , 0.001. In addition to PXR and CAR, multiple other transcription factors, including peroxisome proliferator-activated receptor (PPAR) a and liver X receptor (LXR), upregulate CYP3A4 expression (Drocourt et al, 2002;Duniec-Dmuchowski et al, 2007;Thomas et al, 2013). However, potential involvement of PPARa and LXR in CYP3A4 repression by GW4064 appears unlikely.…”

Nuclear receptors CAR and PXR: Molecular, functional, and biomedical aspects

“…Liver X receptors (LXRa and LXRb) are NRs that coordinate carbohydrate and lipid metabolism by binding oxysterols. Other LXR agonists, such as 24(S),25-epoxycholesterol and T0901317, are shown to induce CYP3A4 and CYP2B6 mRNA expression through the activation of PXR (Duniec-Dmuchowski et al, 2007). The synthetic LXR agonist, T0901317, is also a high-affinity ligand for PXR.…”