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学科主题: 基础医学
题名:
The Role of CYP3A4 mRNA Transcript with Shortened 3 ′-Untranslated Region in Hepatocyte Differentiation, Liver Development, and Response to Drug Induction
作者: Li, Dan1,2; Gaedigk, Roger3; Hart, Steven N.1; Leeder, J. Steven3; Zhong, Xiao-bo1,2
刊名: MOLECULAR PHARMACOLOGY
发表日期: 2012
DOI: 10.1124/mol.111.074393
卷: 81, 期:1, 页:86-96
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: 3&prime ; UNTRANSLATED REGIONS ; CYTOCHROME-P-450 NIFEDIPINE OXIDASE ; POLYADENYLATION SITE SELECTION ; ALTERNATIVE POLYADENYLATION ; HEPARG CELLS ; EXPRESSION ; SEQUENCE ; GENES ; SEQ ; XENOBIOTICS
英文摘要:

Cytochrome P450 3A4 (CYP3A4) metabolizes more than 50% of prescribed drugs. The expression of CYP3A4 changes during liver development and may be affected by the administration of some drugs. Alternative mRNA transcripts occur in more than 90% of human genes and are frequently observed in cells responding to developmental and environmental signals. Different mRNA transcripts may encode functionally distinct proteins or contribute to variability of mRNA stability or protein translation efficiency. The purpose of this study was to examine expression of alternative CYP3A4 mRNA transcripts in hepatocytes in response to developmental signals and drugs. cDNA cloning and RNA sequencing (RNA-Seq) were used to identify CYP3A4 mRNA transcripts. Three transcripts were found in HepaRG cells and liver tissues: one represented a canonical mRNA with full-length 3′-untranslated region (UTR), one had a shorter 3′-UTR, and one contained partial intron-6 retention. The alternative mRNA transcripts were validated by either rapid amplification of cDNA 3′-end or endpoint polymerase chain reaction (PCR). Quantification of the transcripts by RNA-Seq and real time quantitative PCR revealed that the CYP3A4 transcript with shorter 3′-UTR was preferentially expressed in developed livers, differentiated hepatocytes, and in rifampicin- and phenobarbital-induced hepatocytes. The CYP3A4 transcript with shorter 3′-UTR was more stable and produced more protein compared with the CYP3A4 transcript with canonical 3′-UTR. We conclude that the 3′-end processing of CYP3A4 contributes to the quantitative regulation of CYP3A4 gene expression through alternative polyadenylation, which may serve as a regulatory mechanism explaining changes of CYP3A4 expression and activity during hepatocyte differentiation and liver development and in response to drug induction.

语种: 英语
所属项目编号: 1R01-GM087376-01A1 ; 5P20-RR021940 ; 1R01-ES019487-01A1 ; 1R01-ES10855 ; N01-DK7-0004/HHSN26700700004C
项目资助者: National Institutes of Health National Institute of General Medical Sciences ; National Institutes of Health National Center for Research Resources ; National Institutes of Health National Institute for Environmental Health Sciences ; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases
WOS记录号: WOS:000298413500010
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/58602
Appears in Collections:基础医学院_药理学系_期刊论文

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作者单位: 1.Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA
2.Peking Univ, Sch Basic Med Sci, Dept Pharmacol, Beijing 100871, Peoples R China
3.Childrens Mercy Hosp & Clin, Dept Pediat, Div Clin Pharmacol & Med Toxicol, Kansas City, MO USA

Recommended Citation:
Li, Dan,Gaedigk, Roger,Hart, Steven N.,et al. The Role of CYP3A4 mRNA Transcript with Shortened 3 ′-Untranslated Region in Hepatocyte Differentiation, Liver Development, and Response to Drug Induction[J]. MOLECULAR PHARMACOLOGY,2012,81(1):86-96.
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