Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils.
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.
Waring
Jeffrey F
JF
Department of Cellular and Molecular Toxicology, Abbott Laboratories, Bldg. AP9A R463, 100 Abbott Park Road, Abbott Park, IL 60064-6104, USA. jeff.waring@abbott.com
Liguori
Michael J
MJ
Luyendyk
James P
JP
Maddox
Jane F
JF
Ganey
Patricia E
PE
Stachlewitz
Robert F
RF
North
Colin
C
Blomme
Eric A G
EA
Roth
Robert A
RA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D018925:Chemokines / Q000502:physiology*; D019743:Chemokines, CXC / Q000502:physiology; D004357:Drug Synergism; D024841:Fluoroquinolones / Q000633:toxicity*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009287:Naphthyridines / Q000633:toxicity*; D009504:Neutrophils / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D018925:Chemokines; D019743:Chemokines, CXC; D024841:Fluoroquinolones; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009287:Naphthyridines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C080163:trovafloxacin; D000410:Alanine Transaminase