Evidence map›Paper›PMID 34949673›Full record

ArticleDrug metabolism and disposition: the biological fate of chemicals2022

Long Noncoding RNAs Hepatocyte Nuclear Factor 4A Antisense RNA 1 and Hepatocyte Nuclear Factor 1A Antisense RNA 1 Are Involved in Ritonavir-Induced Cytotoxicity in Hepatoma Cells.

Xiaofei Wang, Yihang Yu, Pei Wang, Kun Yang, Yiting Wang, Liang Yan, Xiao-Bo Zhong, Lirong Zhang

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Drug metabolism and disposition: the biological fate of chemicals, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
0.9field-weighted citation impact, top 31% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 17 citations in OpenAlex.

  1. Article
  2. Article
  3. Correlations of Long Noncoding RNA HNF4A-AS1 Alternative Transcripts with Liver Diseases and Drug Metabolism.Drug metabolism and disposition: the biological fate of chemicals · 2024
    Article
  4. Article
  5. Article
  6. Review
  7. Review
  8. Article
  9. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 1 institution in 2 countries.

Xiaofei WangDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).
Yihang YuDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).
Pei WangDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).
Kun YangDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).
Yiting WangDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).
Liang YanDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).
Xiao-Bo ZhongDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.).ORCID 0000-0002-6537-5415
Lirong ZhangDepartment of Pharmacology, School of Basic Medical Sciences (X.W., Y.Y., P.W., K.Y., Y.W., L.Z.) and State Key Laboratory for Esophageal Cancer Prevention and Treatment, (L.Z.) Zhengzhou University, Zhengzhou, China; Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China (L.Y.); and Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (X.-B.Z.) zhanglirongzzu@126.com.
University of Connecticut · US

Funding

The role of lncRNAs in P450-mediated drug metabolism and drug-induced liver injuryR35GM140862 · NIGMS · UNIVERSITY OF CONNECTICUT STORRS · PI ZHONG, XIAO-BO · 2021 to 2025
$2.0M
NIGMS NIH HHS R35 GM140862
6 · The paper itself

Abstract

Ritonavir (RTV), a pharmacoenhancer used in anti-HIV regimens, can induce liver damage. RTV is primarily metabolized by cytochrome P450 3A4 (CYP3A4) in the liver. HNF4A antisense RNA 1 (HNF4A-AS1) and HNF1A antisense RNA 1 (HNF1A-AS1) are long noncoding RNAs that regulate the expression of pregnane X receptor (PXR) and CYP3A4. This study investigated the role and underlying mechanisms of HNF4A-AS1 and HNF1A-AS1 in RTV-induced hepatotoxicity. HNF4A-AS1 and HNF1A-AS1 were knocked down by small hairpin RNAs in Huh7 and HepG2 cells. Lactate dehydrogenase and reactive oxygen species assays were performed to assess RTV-induced hepatotoxicity. Chromatin immunoprecipitation quantitative real-time polymerase chain reaction was used to detect PXR enrichment and histone modifications in the CYP3A4 promoter. HNF4A-AS1 knockdown increased PXR and CYP3A4 expression and exacerbated RTV-induced cytotoxicity, whereas HNF1A-AS1 knockdown generated the opposite phenotype. Mechanistically, enrichment of PXR and trimethylation of histone 3 lysine 4 (H3K4me3) in the CYP3A4 promoter was increased, and trimethylation of histone 3 lysine 27 (H3K27me3) was decreased after HNF4A-AS1 knockdown. However, PXR and H3K4me3 enrichment decreased after HNF1A-AS1 knockdown. Alterations in RTV-induced hepatotoxicity caused by decreasing HNF4A-AS1 or HNF1A-AS1 were reversed by knockdown or overexpression of PXR. Increased susceptibility to RTV-induced liver injury caused by the PXR activator rifampicin was attenuated by HNF4A-AS1 overexpression or HNF1A-AS1 knockdown. Taken together, these results revealed that HNF4A-AS1 and HNF1A-AS1 modulated RTV-induced hepatotoxicity by regulating CYP3A4 expression, primarily by affecting the binding of PXR and histone modification status in the CYP3A4 promoter. SIGNIFICANCE STATEMENT: HNF4A-AS1 and HNF1A-AS1, transcribed separately from neighboring antisense genes of the human transcription factor genes

Indexed as

Carcinoma, HepatocellularChemical and Drug Induced Liver Injury, ChronicLiver NeoplasmsReceptors, SteroidRNA, Long NoncodingCytochrome P-450 CYP3AHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 4HistonesHumansLysineRifampinRitonavirRNA, AntisenseCytochrome P-450 CYP3AHepatocyte Nuclear Factor 1Hepatocyte Nuclear Factor 4HistonesLysineReceptors, SteroidRifampinRitonavirRNA, AntisenseRNA, Long Noncoding

Identifiers

PMID34949673
PMCPMC9132102
OpenAlexW4200479812

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.