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Title: Epigenetic changes in the rat livers induced by pyrazinamide treatment

Abstract

Drug-induced liver injury, including drug-induced hepatotoxicity during the treatment of tuberculosis infection, is a major health problem with increasingly significant challenges to modern hepatology. Therefore, the assessment and monitoring of the hepatotoxicity of antituberculosis drugs for prevention of liver injury are great concerns during disease treatment. The recently emerged data showing the ability of toxicants, including pharmaceutical agents, to alter cellular epigenetic status, open a unique opportunity for early detection of drug hepatotoxicity. Here we report that treatment of male Wistar rats with antituberculosis drug pyrazinamide at doses of 250, 500 or 1000 mg/kg/day body weight for 45 days leads to an early and sustained decrease in cytosine DNA methylation, progressive hypomethylation of long interspersed nucleotide elements (LINE-1), and aberrant promoter hypermethylation of placental form glutathione-S-transferase (GSTP) and p16{sup INK4A} genes in livers of pyrazinamide-treated rats, while serum levels of bilirubin and activity of aminotransferases changed modestly. The early occurrence of these epigenetic alterations and their association with progression of liver injury specific pathological changes indicate that alterations in DNA methylation may be useful predictive markers for the assessment of drug hepatotoxicity.

Authors:
 [1];  [2]; ; ; ;  [1]
  1. Institute of Pharmacology and Toxicology of the Academy of Medical Sciences of Ukraine, Kyiv (Ukraine)
  2. National Center for Toxicological Research, Jefferson, AR (United States)
Publication Date:
OSTI Identifier:
21077876
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 225; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2007.08.011; PII: S0041-008X(07)00373-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AMINOTRANSFERASES; BILIRUBIN; CYTOSINE; DNA; GLUTATHIONE; INJURIES; LIVER; METHYLATION; NUCLEOTIDES; PATHOLOGICAL CHANGES; RATS; TUBERCULOSIS

Citation Formats

Kovalenko, V M, Bagnyukova, T V, Sergienko, O V, Bondarenko, L B, Shayakhmetova, G M, Matvienko, A V, and Pogribny, I.P. Epigenetic changes in the rat livers induced by pyrazinamide treatment. United States: N. p., 2007. Web. doi:10.1016/j.taap.2007.08.011.
Kovalenko, V M, Bagnyukova, T V, Sergienko, O V, Bondarenko, L B, Shayakhmetova, G M, Matvienko, A V, & Pogribny, I.P. Epigenetic changes in the rat livers induced by pyrazinamide treatment. United States. https://doi.org/10.1016/j.taap.2007.08.011
Kovalenko, V M, Bagnyukova, T V, Sergienko, O V, Bondarenko, L B, Shayakhmetova, G M, Matvienko, A V, and Pogribny, I.P. 2007. "Epigenetic changes in the rat livers induced by pyrazinamide treatment". United States. https://doi.org/10.1016/j.taap.2007.08.011.
@article{osti_21077876,
title = {Epigenetic changes in the rat livers induced by pyrazinamide treatment},
author = {Kovalenko, V M and Bagnyukova, T V and Sergienko, O V and Bondarenko, L B and Shayakhmetova, G M and Matvienko, A V and Pogribny, I.P.},
abstractNote = {Drug-induced liver injury, including drug-induced hepatotoxicity during the treatment of tuberculosis infection, is a major health problem with increasingly significant challenges to modern hepatology. Therefore, the assessment and monitoring of the hepatotoxicity of antituberculosis drugs for prevention of liver injury are great concerns during disease treatment. The recently emerged data showing the ability of toxicants, including pharmaceutical agents, to alter cellular epigenetic status, open a unique opportunity for early detection of drug hepatotoxicity. Here we report that treatment of male Wistar rats with antituberculosis drug pyrazinamide at doses of 250, 500 or 1000 mg/kg/day body weight for 45 days leads to an early and sustained decrease in cytosine DNA methylation, progressive hypomethylation of long interspersed nucleotide elements (LINE-1), and aberrant promoter hypermethylation of placental form glutathione-S-transferase (GSTP) and p16{sup INK4A} genes in livers of pyrazinamide-treated rats, while serum levels of bilirubin and activity of aminotransferases changed modestly. The early occurrence of these epigenetic alterations and their association with progression of liver injury specific pathological changes indicate that alterations in DNA methylation may be useful predictive markers for the assessment of drug hepatotoxicity.},
doi = {10.1016/j.taap.2007.08.011},
url = {https://www.osti.gov/biblio/21077876}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 225,
place = {United States},
year = {Sat Dec 15 00:00:00 EST 2007},
month = {Sat Dec 15 00:00:00 EST 2007}
}