PT  - JOURNAL ARTICLE
AU  - Jeffrey F. Waring
AU  - Michael J. Liguori
AU  - James P. Luyendyk
AU  - Jane F. Maddox
AU  - Patricia E. Ganey
AU  - Robert F. Stachlewitz
AU  - Colin North
AU  - Eric A. G. Blomme
AU  - Robert A. Roth
TI  - Microarray Analysis of Lipopolysaccharide Potentiation of Trovafloxacin-Induced Liver Injury in Rats Suggests a Role for Proinflammatory Chemokines and Neutrophils
AID  - 10.1124/jpet.105.096347
DP  - 2006 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1080--1087
VI  - 316
IP  - 3
4099  - http://jpet.aspetjournals.org/content/316/3/1080.short
4100  - http://jpet.aspetjournals.org/content/316/3/1080.full
SO  - J Pharmacol Exp Ther2006 Mar 01; 316
AB  - Idiosyncratic drug toxicity refers to toxic reactions occurring in a small subset of patients and usually cannot be predicted during preclinical or early phases of clinical trials. One hypothesis for the pathogenesis of hepatic idiosyncratic drug reactions is that, in certain individuals, underlying inflammation results in sensitization of the liver, such that injury occurs from an agent that typically would not cause hepatotoxicity at a therapeutic dose. We explored this possibility by cotreating rats with nonhepatotoxic doses of bacterial lipopolysaccharide (LPS) and trovafloxacin (TVX), a drug that caused idiosyncratic hepatotoxicity in humans. The combination of LPS and TVX resulted in hepatotoxicity in rats, as determined by increases in serum alanine aminotransferase activity and hepatocellular necrosis, which were not observed with either agent alone. In contrast, treatment with LPS and levofloxacin, a fluoroquinolone without human idiosyncratic liability, did not result in these changes. Liver gene expression analysis identified unique changes induced by the combination of TVX and LPS, including enhanced expression of chemokines, suggestive of liver neutrophil (PMN) accumulation and activation. Consistent with a role for PMN in the hepatotoxicity induced by LPS/TVX, prior depletion of PMN attenuated the liver injury. The results suggest that gene expression profiles predictive of idiosyncratic liability can be generated in rats cotreated with LPS and drug. Furthermore, they identify gene expression changes that could be explored as biomarkers for idiosyncratic toxicity and lead to enhanced understanding of the mechanism(s) underlying hepatotoxicity induced by TVX.