Regulation of BCRP expression and sulfasalazine pharmacokinetics by the nuclear receptor REV-ERBα

Abstract

1. BCRP (breast cancer resistance protein) is a crucial efflux transporter involved in the regulation of the pharmacokinetics and pharmacodynamics of a wide range of drugs. Herein, we aimed to investigate a potential role for the nuclear receptor REV-ERBα in the regulation of BCRP expression and sulfasalazine (a BCRP probe substrate) pharmacokinetics.

2. Regulation of BCRP expression by REV-ERBα was assessed using Rev-erbα^-/- mice and AML12 and CT26 cells. Pharmacokinetic analysis was performed with Rev-erbα^-/- and wild-type mice after sulfasalazine administration.

3. We found that the expression levels of BCRP mRNA and protein were downregulated in the liver and small intestine of Rev-erbα-dificient mice. In line with this, Rev-erbα ablation increased the systemic exposures of oral sulfasalazine.

4. Positive regulation of BCRP expression and function by REV-ERBα was furtherly confirmed in AML12 and CT26 cells. Moreover, indirect regulation of Bcrp expression by REV-ERBα was potentially mediated by a negative transcription factor DEC2, which is a downstream target of REV-ERBα.

5. In conclusion, REV-ERBα positively regulates BCRP expression in mice, thereby affecting sulfasalazine pharmacokinetics.

Keywords:

• REV-ERBα
• BCRP
• sulfasalazine
• pharmacokinetics
• gene regulation

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported by the scientific research and cultivation fund of the Affiliated Shunde Hospital of Jinan University (No. 202101007), the Medical Research Project of Foshan Health Bureau (No. 20220290), the Guangdong Basic and Applied Basic Research Foundation (Nos. 2021A1515011256 and 2023A1515030140) and the Science and Technology Projects in Guangzhou (No. 202201011284).