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Epigenetic changes in the rat livers induced by pyrazinamide treatment.

Authors: Kovalenko, VM  Bagnyukova, TV  Sergienko, OV  Bondarenko, LB  Shayakhmetova, GM  Matvienko, AV  Pogribny, IP 
Citation: Kovalenko VM, etal., Toxicol Appl Pharmacol. 2007 Dec 15;225(3):293-9. Epub 2007 Aug 23.
Pubmed: (View Article at PubMed) PMID:17920094
DOI: Full-text: DOI:10.1016/j.taap.2007.08.011

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(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.


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CRRD Object Information
CRRD ID: 2289693
Created: 2008-02-07
Species: All species
Last Modified: 2008-02-07
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.