Role of Multiple MicroRNAs in the Sexually Dimorphic Expression of Cyp2b9 in Mouse Liver

doi:10.1124/dmd.113.052217

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	Role of Multiple MicroRNAs in the Sexually Dimorphic Expression of Cyp2b9 in Mouse Liver
	Xie, Xiaofeng 2; Miao, Lingling 2; Yao, Jun 2; Feng, Chenchen 2; Li, Chenggang 2; Gao, Man 2; Liu, Mingxia 2; Gong, Likun2 ; Wang, Yizheng 1; Qi, Xinming2
刊名	DRUG METABOLISM AND DISPOSITION
	2013-10
卷号	41 期号:10 页码:1732-1737
ISSN号	0090-9556
DOI	10.1124/dmd.113.052217
文献子类	Article
英文摘要	Mouse cytochrome P450 2b9 (Cyp2b9) is a testosterone 16 alpha-hydroxylase enzyme showing female-specific expression in many inbred mouse strains, including C57BL/6J. Previous studies have recognized that some sex-dependently secreted endogenous modulating factors were involved in the sexually dimorphic expression of Cyp2b9 through transcriptional regulation. In this study, we found evidence that some microRNAs contributed to the sexually biased expression of Cyp2b9 via post-transcriptional regulation. Cyp2b9 was upregulated in livers of hepatocyte-specific Dicer1 knockout mice at 3 weeks. The age-dependent downregulation of Cyp2b9 in the livers of male mice was diminished when Dicer1 was specifically knocked out in hepatocytes. When these data were combined with bioinformatics analysis and microRNA profiles of male and female mice, we found that 18 microRNAs were associated with the sexually dimorphic expression of Cyp2b9, which showed higher expression levels in male C57BL/6J mice when compared with females. Luciferase assays revealed that approximate half of these microRNAs repressed luciferase activity in a reporter system containing the 39-untranslated region (39-UTR) of Cyp2b9, and also inhibited Cyp2b9 protein expression. MicroRNA seed region mutation or mutations in putative binding sites of the microRNAs in Cyp2b9 39-UTR led to the loss of the suppression of luciferase activity. There was also a negative correlation between the levels of these microRNAs and Cyp2b9. Our results suggested that multiple microRNAs participated in the regulation of Cyp2b9 expression, and that the lower expression levels of these microRNAs potentially contributed to the female-specific expression of Cyp2b9 in the livers of C57BL/6J mice.
资助项目	National Science and Technology Major Project[2012ZX09302-003] ; National Science and Technology Major Project[2012ZX09301-001-006]
WOS关键词	GENE-EXPRESSION ; SEX-DIFFERENCES ; PHARMACOLOGICAL RESPONSE ; ENZYMES ; PHARMACOKINETICS ; METABOLISM ; GROWTH ; MICE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000324523100003
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277447]
专题	药物安全性评价中心
通讯作者	Qi, Xinming
作者单位	1.Chinese Acad Sci, Inst Neurosci, Lab Neural Signal Transduct, Shanghai, Peoples R China 2.Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xie, Xiaofeng,Miao, Lingling,Yao, Jun,et al. Role of Multiple MicroRNAs in the Sexually Dimorphic Expression of Cyp2b9 in Mouse Liver[J]. DRUG METABOLISM AND DISPOSITION,2013,41(10):1732-1737.
APA	Xie, Xiaofeng.,Miao, Lingling.,Yao, Jun.,Feng, Chenchen.,Li, Chenggang.,...&Ren, Jin.(2013).Role of Multiple MicroRNAs in the Sexually Dimorphic Expression of Cyp2b9 in Mouse Liver.DRUG METABOLISM AND DISPOSITION,41(10),1732-1737.
MLA	Xie, Xiaofeng,et al."Role of Multiple MicroRNAs in the Sexually Dimorphic Expression of Cyp2b9 in Mouse Liver".DRUG METABOLISM AND DISPOSITION 41.10(2013):1732-1737.