PMID- 37532539
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20231109
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Print)
IS  - 0090-9556 (Linking)
VI  - 51
IP  - 11
DP  - 2023 Nov
TI  - A Comprehensive Evaluation of the Effects of RNA-Editing Proteins ADAR and ADARB1 
      on the Expression of the Drug-Metabolizing Enzymes in HepaRG Cells.
PG  - 1508-1514
LID - 10.1124/dmd.123.001396 [doi]
AB  - Two RNA-editing proteins, the adenosine deaminase acting on RNA, ADAR, and 
      ADARB1, broadly regulate gene expression in editing-dependent and 
      editing-independent manners. Previous studies showed that the expression of the 
      drug-metabolizing cytochrome P450s (P450s) and UDP glucuronosyltransferases 
      (UGTs) changes upon knockdown (KD) of ADAR or ADARB1 in different hepatic cell 
      lines. To systematically survey the effects of these two ADARs on the expression 
      of P450s and UGTs, we used small interfering RNA in HepaRG cells and tested the 
      association between the expression of the P450s and ADARs in a liver sample 
      cohort (n = 246). KD of ADAR increased the expression of the CYP3As and CYP2C9 
      and reduced the expression of the others, whereas KD of ADARB1 reduced the 
      expression of nearly all genes tested. ADAR KD also suppressed the induction of 
      most P450s, whereas ADARB1 KD had mixed effects depending on the inducer/gene 
      combination. P450 expression was positively associated with both ADARs in liver 
      samples, consistent with the KD results. However, after adjusting for the 
      expression of transcription factors (TFs) known to regulate P450 expression, the 
      associations disappeared, indicating that the effects of ADAR or ADARB1 primarily 
      occur through TFs. Moreover, we found that the expression of normally spliced 
      CYP3A5 transcripts is increased in both KDs, indicating a direct effect of the 
      ADARs on promoting the usage of the cryptic splice site generated by CYP3A5*3. 
      Taken together, our results revealed the nonoverlapping regulatory effects of 
      ADAR and ADARB1 and supported their broad roles in controlling the expression of 
      drug-metabolizing enzymes in the liver. SIGNIFICANCE STATEMENT: Here, this study 
      systematically surveyed the roles of ADAR and ADARB1 in both basal and induced 
      expression of drug-metabolizing enzymes and assessed their coexpression in liver 
      samples. This study's results support that ADAR and ADARB1 regulate the 
      expression of the drug-metabolizing enzymes in the liver, suggesting that factors 
      affecting ADAR expression also have the potential to impact drug metabolism.
CI  - Copyright (c) 2023 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Collins, Joseph M
AU  - Collins JM
AUID- ORCID: 0000-0003-4070-3598
AD  - Department of Pharmacotherapy and Translational Research, College of Pharmacy, 
      Center for Pharmacogenomics, University of Florida, Gainesville, Florida.
FAU - Wang, Danxin
AU  - Wang D
AUID- ORCID: 0000-0002-7134-3065
AD  - Department of Pharmacotherapy and Translational Research, College of Pharmacy, 
      Center for Pharmacogenomics, University of Florida, Gainesville, Florida 
      danxin.wang@cop.ufl.edu.
LA  - eng
GR  - R35 GM140845/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230802
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - 63231-63-0 (RNA)
RN  - 0 (Transcription Factors)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 3.5.4.4 (ADARB1 protein, human)
RN  - EC 3.5.4.4 (Adenosine Deaminase)
RN  - 0 (RNA-Binding Proteins)
SB  - IM
MH  - Humans
MH  - *Cytochrome P-450 CYP3A/metabolism
MH  - *RNA
MH  - Hepatocytes/metabolism
MH  - Liver/metabolism
MH  - Transcription Factors/metabolism
MH  - Cytochrome P-450 Enzyme System/genetics/metabolism
MH  - Adenosine Deaminase/genetics/metabolism
MH  - RNA-Binding Proteins/genetics/metabolism
PMC - PMC10586505
EDAT- 2023/08/03 01:06
MHDA- 2023/10/23 12:44
PMCR- 2024/11/01
CRDT- 2023/08/02 21:38
PHST- 2023/05/15 00:00 [received]
PHST- 2023/07/24 00:00 [accepted]
PHST- 2024/11/01 00:00 [pmc-release]
PHST- 2023/10/23 12:44 [medline]
PHST- 2023/08/03 01:06 [pubmed]
PHST- 2023/08/02 21:38 [entrez]
AID - dmd.123.001396 [pii]
AID - DMD_AR2023001396 [pii]
AID - 10.1124/dmd.123.001396 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2023 Nov;51(11):1508-1514. doi: 10.1124/dmd.123.001396. Epub 
      2023 Aug 2.