Comparison of TNFα to Lipopolysaccharide as an Inflammagen to Characterize the Idiosyncratic Hepatotoxicity Potential of Drugs: Trovafloxacin as an Example

Idiosyncratic drug reactions (IDRs) are poorly understood, unpredictable, and not detected in preclinical studies. Although the cause of these reactions is likely multifactorial, one hypothesis is that an underlying inflammatory state lowers the tolerance to a xenobiotic. Previously used in an inflammation IDR model, bacterial lipopolysaccharide (LPS) is heterogeneous in nature, making development of standardized testing protocols difficult. Here, the use of rat tumor necrosis factor-alpha (TNF alpha) to replace LPS as an inflammatory stimulus was investigated. Sprague-Dawley rats were treated with separate preparations of LPS or TNF alpha, and hepatic transcriptomic effects were compared. TNF alpha showed enhanced consistency at the transcriptomic level compared to LPS. TNF alpha and LPS regulated similar biochemical pathways, although LPS was associated with more robust inflammatory signaling than TNF alpha. Rats were then codosed with TNF alpha and trovafloxacin (TVX), an IDR-associated drug, and evaluated by liver histopathology, clinical chemistry, and gene expression analysis. TNF alpha/TVX induced unique gene expression changes that clustered separately from TNF alpha/levofloxacin, a drug not associated with IDRs. TNF alpha/TVX cotreatment led to autoinduction of TNF alpha resulting in potentiation of underlying gene expression stress signals. Comparison of TNF alpha/TVX and LPS/TVX gene expression profiles revealed similarities in the regulation of biochemical pathways. In conclusion, TNF alpha could be used in lieu of LPS as an inflammatory stimulus in this model of IDRs.