Cargando…

Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog

Nucleoside analogues (NAs) have been the most frequently used treatment option for chronic hepatitis B patients. However, they may have genotoxic potentials due to their interference with nucleic acid metabolism. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs a...

Descripción completa

Detalles Bibliográficos
Autores principales: Jiang, Lei, Wu, Xiaohua, He, Fang, Liu, Ying, Hu, Xiaoqing, Takeda, Shunichi, Qing, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723259/
https://www.ncbi.nlm.nih.gov/pubmed/26800464
http://dx.doi.org/10.1371/journal.pone.0147440
_version_ 1782411484320497664
author Jiang, Lei
Wu, Xiaohua
He, Fang
Liu, Ying
Hu, Xiaoqing
Takeda, Shunichi
Qing, Yong
author_facet Jiang, Lei
Wu, Xiaohua
He, Fang
Liu, Ying
Hu, Xiaoqing
Takeda, Shunichi
Qing, Yong
author_sort Jiang, Lei
collection PubMed
description Nucleoside analogues (NAs) have been the most frequently used treatment option for chronic hepatitis B patients. However, they may have genotoxic potentials due to their interference with nucleic acid metabolism. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs against hepatitis B virus. It has reported that entecavir gave positive responses in both genotoxicity and carcinogenicity assays. However the genotoxic mechanism of entecavir remains elusive. To evaluate the genotoxic mechanisms, we analyzed the effect of entecavir on a panel of chicken DT40 B-lymphocyte isogenic mutant cell line deficient in DNA repair and damage tolerance pathways. Our results showed that Parp1(-/-) mutant cells defective in single-strand break (SSB) repair were the most sensitive to entecavir. Brca1(-/-), Ubc13(-/-) and translesion-DNA-synthesis deficient cells including Rad18(-/-) and Rev3(-/-) were hypersensitive to entecavir. XPA(-/-) mutant deficient in nucleotide excision repair was also slightly sensitive to entecavir. γ-H2AX foci forming assay confirmed the existence of DNA damage by entecavir in Parp1(-/-), Rad18(-/-) and Brca1(-/-) mutants. Karyotype assay further showed entecavir-induced chromosomal aberrations, especially the chromosome gaps in Parp1(-/-), Brca1(-/-), Rad18(-/-) and Rev3(-/-) cells when compared with wild-type cells. These genetic comprehensive studies clearly identified the genotoxic potentials of entecavir and suggested that SSB and postreplication repair pathways may suppress entecavir-induced genotoxicity.
format Online
Article
Text
id pubmed-4723259
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-47232592016-01-30 Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog Jiang, Lei Wu, Xiaohua He, Fang Liu, Ying Hu, Xiaoqing Takeda, Shunichi Qing, Yong PLoS One Research Article Nucleoside analogues (NAs) have been the most frequently used treatment option for chronic hepatitis B patients. However, they may have genotoxic potentials due to their interference with nucleic acid metabolism. Entecavir, a deoxyguanosine analog, is one of the most widely used oral antiviral NAs against hepatitis B virus. It has reported that entecavir gave positive responses in both genotoxicity and carcinogenicity assays. However the genotoxic mechanism of entecavir remains elusive. To evaluate the genotoxic mechanisms, we analyzed the effect of entecavir on a panel of chicken DT40 B-lymphocyte isogenic mutant cell line deficient in DNA repair and damage tolerance pathways. Our results showed that Parp1(-/-) mutant cells defective in single-strand break (SSB) repair were the most sensitive to entecavir. Brca1(-/-), Ubc13(-/-) and translesion-DNA-synthesis deficient cells including Rad18(-/-) and Rev3(-/-) were hypersensitive to entecavir. XPA(-/-) mutant deficient in nucleotide excision repair was also slightly sensitive to entecavir. γ-H2AX foci forming assay confirmed the existence of DNA damage by entecavir in Parp1(-/-), Rad18(-/-) and Brca1(-/-) mutants. Karyotype assay further showed entecavir-induced chromosomal aberrations, especially the chromosome gaps in Parp1(-/-), Brca1(-/-), Rad18(-/-) and Rev3(-/-) cells when compared with wild-type cells. These genetic comprehensive studies clearly identified the genotoxic potentials of entecavir and suggested that SSB and postreplication repair pathways may suppress entecavir-induced genotoxicity. Public Library of Science 2016-01-22 /pmc/articles/PMC4723259/ /pubmed/26800464 http://dx.doi.org/10.1371/journal.pone.0147440 Text en © 2016 Jiang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jiang, Lei
Wu, Xiaohua
He, Fang
Liu, Ying
Hu, Xiaoqing
Takeda, Shunichi
Qing, Yong
Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog
title Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog
title_full Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog
title_fullStr Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog
title_full_unstemmed Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog
title_short Genetic Evidence for Genotoxic Effect of Entecavir, an Anti-Hepatitis B Virus Nucleotide Analog
title_sort genetic evidence for genotoxic effect of entecavir, an anti-hepatitis b virus nucleotide analog
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723259/
https://www.ncbi.nlm.nih.gov/pubmed/26800464
http://dx.doi.org/10.1371/journal.pone.0147440
work_keys_str_mv AT jianglei geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog
AT wuxiaohua geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog
AT hefang geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog
AT liuying geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog
AT huxiaoqing geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog
AT takedashunichi geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog
AT qingyong geneticevidenceforgenotoxiceffectofentecaviranantihepatitisbvirusnucleotideanalog