title: Significant increases in the levels of liver enzymes in mice treated with anti-tuberculosis drugs.
abstract: Besides the long-term effectiveness of a given compound, safety is a very important feature to consider when developing new compounds for chemotherapy against tuberculosis. Reports of fatal and severe liver injury associated with rifampicin-pyrazinamide (RIF-PZA) treatment regimens for latent tuberculosis infections prompted this study to evaluate whether a mouse model has any potential as a tool to assess liver injury following extensive exposure to tuberculosis drugs. Mice were administered high doses of existing drug regimens for latent tuberculosis over a relatively short time period. Alanine aminotransferase (ALT), aspartate aminotransferase and bilirubin levels were determined after 2 weeks and 4 weeks of treatment in serum samples collected from uninfected mice as well as mice infected with Mycobacterium tuberculosis. ALT levels increased significantly after a RIF-PZA treatment regimen for 4 weeks in uninfected mice and after 2 weeks in infected mice. Bilirubin serum levels were also significantly elevated in the M. tuberculosis-infected mice after 4 weeks of RIF-PZA treatment. The data obtained indicate that changes in serum enzyme levels in mice after extensive exposure to tuberculosis drugs could be useful as an initial indicator of drug-related hepatotoxicity.
authors.affiliation: Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA. lenaerts@colostate.edu
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Christine M
authors.initials: CM
authors.lastname: Johnson
authors.forename: Karen S
authors.initials: KS
authors.lastname: Marrieta
authors.forename: Veronica
authors.initials: V
authors.lastname: Gruppo
authors.forename: Ian M
authors.initials: IM
authors.lastname: Orme
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism*; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D011718:Pyrazinamide / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D012293:Rifampin / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D000410:Alanine Transaminase; D012293:Rifampin