BDE47 induces rat CYP3A1 by targeting the transcriptional regulation of miR-23b.

Zhenzhen Sun,Jun Gu,Shou-Lin Wang,Hongbao Yang,Chao Wang,Yongquan Yu,Lu Yang,Weimin Gao,Zhan Zhang,Meghan Cromie,Minghui Ji

doi:10.1038/srep31958

Abstract

Cytochrome P450 3A (CYP3A) is the most abundant CYP450 enzyme in the liver and is involved in the metabolism of over 50% of xenobiotics. Our previous studies revealed that 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) could induce rat CYP3A1 expression, but the molecular basis remains unclear. Using in silico analysis, we identified a potential miR-23b recognition element (MRE23b) in the 3′-UTR region of CYP3A1 mRNA, which was verified by the luciferase assay. The miR-23b mimic and inhibitor significantly down- and up-regulated the expression of CYP3A1, respectively. Additionally, BDE47 significantly down-regulated the expression of miR-23b in rats and in hepatic H4IIE cells. Induction or blockage of CYP3A1 by a miR-23b inhibitor or mimic could correspondingly alter BDE47-induced expression of CYP3A1 and cytotoxicity in H4IIE cells. Furthermore, LV-anti-miR-23b significantly decreased endogenous levels of miR-23b and increased the expression and activity of CYP3A1 in rat liver. LV-anti-miR-23b also significantly increased the hydroxylated metabolites of BDE47 (3-OH-BDE47, 4-OH-BDE42, and 4′-OH-BDE49) in rat serum. In conclusion, we first found that BDE47 induced rat CYP3A1 expression by targeting the transcriptional regulation of miR-23b. This study helps provide a better understanding of CYP3A regulation and offers novel clues for the role of miRNAs in the metabolism and distribution of environmental pollutants.

Highlights

It is well known that the liver is a central organ in the regulation of diverse processes, among which the metabolism, secretion, storage, and detoxification of endogenous and exogenous substances are prominent[1]
BDE47 dose-dependently increased CYP3A1 mRNA (Fig. 1A) and protein expression (Fig. 1B), both of which were aggravated by DEX
Based on in vitro and in vivo experiments, we first investigated the role of miR-23b in the BDE47-induced expression and activity of CYP3A1

Summary

Introduction

It is well known that the liver is a central organ in the regulation of diverse processes, among which the metabolism, secretion, storage, and detoxification of endogenous and exogenous substances are prominent[1]. The importance of microRNAs (miRNAs) in regulating CYPs and nuclear receptors or other transcription factors is beginning to be recognized. Dexamethasone (DEX) could markedly increase the expression and enzymatic activity of CYP3A1 through PXR in healthy and cirrhotic rats, irrespective of the degree of liver dysfunction[8]. Our previous study demonstrated that BDE47 increased the expression of CYP3A1 in rat liver, and in turn affected CYP3A1-mediated metabolic activation of BDE4714. We first examined the metabolic activation of BDE47 by CYP3A1. We validated the regulation of miR-23b in BDE47-induced expression and activity of CYP3A1 in in vitro and in vivo experiments. This study may provide a better understanding of CYP3A regulation and offer novel clues for the role of miRNAs in the metabolism and distribution of drugs and environmental pollutants

Methods

Results

Conclusion