Constitutive Androstane Receptor-Mediated Inhibition of Metformin on Phase II Metabolic Enzyme SULT2A1

Xiaowen Hu; Mengsiyu Li; Chunxue Zhang; Shuguang Pang

doi:10.1155/2021/8867218

Constitutive Androstane Receptor-Mediated Inhibition of Metformin on Phase II Metabolic Enzyme SULT2A1

Int J Endocrinol. 2021 Feb 15:2021:8867218. doi: 10.1155/2021/8867218. eCollection 2021.

Authors

Xiaowen Hu^{1

2}, Mengsiyu Li³, Chunxue Zhang⁴, Shuguang Pang^{1

5}

Affiliations

¹ Department of Endocrinology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Department of Infectious Diseases, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
³ Department of Ultrasound, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
⁴ Department of Nuclear Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
⁵ Department of Endocrinology, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China.

Abstract

Background: Metformin, as a first-line treatment for diabetes, interacts with many protein kinases and transcription factors which affect the expression of downstream target genes governing drug metabolism. Sulfotransferase, SULT2A1, one phase II metabolic enzyme, sulfonates both xenobiotic and endobiotic compounds to accelerate drug excretion. Herein, we designed experiments to investigate the effects and mechanisms of metformin on SULT2A1 expression in vitro.

Methods: The hepatocellular carcinoma cell line, HepaRG, was cultured with different concentrations of metformin. The cell viability was measured using CCK8 kit. HepaRG was used to evaluate the protein expression of pregnane X receptor (PXR), the constitutive androstane receptor (CAR), SULT2A1, AMP-activated protein kinase (AMPK), and phosphorylation of AMPK (p-AMPK), respectively, at different concentrations of metformin with or without rifampin (human PXR activator) and CITCO (human CAR activator). The coregulators with CAR on SULT2A1 promoter response elements have also been characterized.

Results: We showed that metformin did not affect the basic expression of SULT2A1 but could suppress the expression of SULT2A1 induced by the activator of human CAR. Investigations revealed that metformin which could block CAR nuclear translocation further suppress SULT2A1. In addition, we found that the prevented CAR transfer into the nucleus by metformin was partially an AMPK-dependent event.

Conclusion: The present study indicated that the activation of AMPK-CAR pathway mediated the suppression of SULT2A1 by metformin. Metformin may affect the metabolism and clearance of drugs which are SULT2A1 substrates. The results that emerged from this work provide substantial insights into an appropriate medication in the treatment of diabetes patients.