Journal
MOLECULAR PHARMACOLOGY
Volume 81, Issue 1, Pages 86-96Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.111.074393
Keywords
-
Categories
Funding
- National Institutes of Health National Institute of General Medical Sciences [1R01-GM087376-01A1]
- National Institutes of Health National Center for Research Resources [5P20-RR021940]
- National Institutes of Health National Institute for Environmental Health Sciences [1R01-ES019487-01A1, 1R01-ES10855]
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [N01-DK7-0004/HHSN26700700004C]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available