Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin.
Idiosyncratic drug toxicity, defined as toxicity that is dose independent, host dependent, and usually cannot be predicted during preclinical or early phases of clinical trials, is a particularly confounding complication of drug development. An understanding of the mechanisms that lead to idiosyncratic liver toxicity would be extremely beneficial for the development of new compounds. We used microarray analysis on isolated human hepatocytes to understand the mechanisms underlying the idiosyncratic toxicity induced by trovafloxacin. Our results clearly distinguish trovafloxacin from other marketed quinolone agents and identify unique gene changes induced by trovafloxacin that are involved in mitochondrial damage, RNA processing, transcription, and inflammation that may suggest a mechanism for the hepatotoxicity induced by this agent. In conclusion, this work establishes the basis for future microarray analysis of new compounds to determine the presence of these expression changes and their usefulness in predicting idiosyncratic hepatotoxicity. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience. Wiley.com/jpages/0270-9139/suppmat/index.htnd).
Liguori
Michael J
MJ
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6104, USA.
Anderson
Mark G
MG
Bukofzer
Stanley
S
McKim
James
J
Pregenzer
Jeffrey F
JF
Retief
Jacques
J
Spear
Brian B
BB
Waring
Jeffrey F
JF
D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D024841:Fluoroquinolones / Q000506:poisoning*; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D046228:Microarray Analysis; D008928:Mitochondria / Q000187:drug effects; D009287:Naphthyridines / Q000506:poisoning*; D018384:Oxidative Stress; D012313:RNA / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000187:drug effects
D024841:Fluoroquinolones; D009287:Naphthyridines; D012313:RNA; C080163:trovafloxacin; D005978:Glutathione