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

نویسندگان

  • Lei Jiang
  • Xiaohua Wu
  • Fang He
  • Ying Liu
  • Xiaoqing Hu
  • Shunichi Takeda
  • Yong Qing
  • Michael R Volkert
چکیده

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.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Entecavir treatment of chronic hepatitis D.

BACKGROUND Hepatitis D virus (HDV) requires hepatitis B surface antigen (HBsAg) to propagate infection and cause disease. Entecavir is a nucleoside analog with potent antiviral efficacy, and in the woodchuck animal model it also decreased hepatitis B virus (HBV) cccDNA and woodchuck surface antigen. The aim of this study was to investigate the efficacy of entecavir in chronic hepatitis D (CHD)....

متن کامل

Hepatitis B Virus Surface Antigen Variants Clustered Within Immune Epitopes in Chronic Hepatitis B Carriers from Hormozgan Province, South of Iran

Objective(s) The aim of this study was to characterize the hepatitis B virus surface protein genotypes and sequence variations among hepatitis B virus surface antigen (HBsAg) positive chronic patients in Hormozgan province, south of Iran. Materials and Methods A total of 8 patients enrolled in this study. The surface gene was amplified and directly sequenced. Genotypes and nucleotide/amino a...

متن کامل

Efficacy and safety of tenofovir in a kidney transplant patient with chronic hepatitis B and nucleos(t)ide multidrug resistance: a case report

INTRODUCTION Five nucleos(t)ide analogs are used to treat chronic hepatitis B. Ideal nucleos(t)ide analog therapy in chronic hepatitis B patients with kidney transplantation must ensure virological suppression and minimize renal injury. However, resistance to nucleos(t)ide analogs frequently results in virological breakthrough, hepatitis flare, and complicated deterioration of the transplanted ...

متن کامل

بررسی ارتباط پلی‌مورفیسم (rs1800872A/C) ژن اینترلوکین 10 با ابتلا به عفونت مزمن هپاتیت B

Background and Aim: Cytokines are believed to play an important role in the regulation of cellular immune response in hepatitis B virus infection. Interleukin 10 is a member of cytokine family. The overall expression of these molecules is mainly controlled by single nucleotide polymorphisms at specific sites on the promoter region of the Interleukin 10 gene. The aim of this study was to a...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:

دوره 11  شماره 

صفحات  -

تاریخ انتشار 2016