Microarray analysis in human hepatocytes suggests a mechanism for hepatotoxicity induced by trovafloxacin

Abstract

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.

Effects of substituents on the NMR features of basic bicyclic ring systems of fluoroquinolone antibiotics and the relationships between NMR chemical shifts, molecular descriptors and drug-likeness parameters

“…Thus Liguori et al (2005) used a method of microarray analysis on isolated human hepatocytes by which they clearly distinguished between TVA and other marketed quinolone agents, and identified unique gene changes induced by TVA that are involved in mitochondrial damage, RNA processing, transcription, and inflammation, which may suggest a possible mechanism for the hepatotoxicity induced by this agent (8). Sun et al (9,10) suggested a model of a cyclopropylamine-containing system that implies oxidation of cyclopropylamine moiety to reactive ring-opened intermediates with a carbon-centered radical, which can be subsequently converted to a,b-unsaturated aldehyde.…”

“…Recently, the possible mechanisms of TVA hepatotoxicity were discussed in several papers (8)(9)(10). Thus Liguori et al (2005) used a method of microarray analysis on isolated human hepatocytes by which they clearly distinguished between TVA and other marketed quinolone agents, and identified unique gene changes induced by TVA that are involved in mitochondrial damage, RNA processing, transcription, and inflammation, which may suggest a possible mechanism for the hepatotoxicity induced by this agent (8).…”

Trovafloxacin-Induced Gene Expression Changes in Liver-Derived in Vitro Systems: Comparison of Primary Human Hepatocytes to HepG2 Cells

“…One exception is trovafloxacin, the use of which has been restricted because of hepatic idiosyncratic drug reaction (IDR) issues (Bertino and Fish, 2000). Our laboratory has previously demonstrated that microarray analysis can distinguish trovafloxacin from other quinolones not associated with hepatic toxicity in PHH (Liguori et al, 2005). Since then, other examples of unique gene expression patterns in PHH or other culture systems from IDRcausing drugs relative to pharmacologically related compounds have been reported (Kier et al, 2004;Guo et al, 2006).…”

“…Moreover, human hepatocytes are subject to various stimuli such as exposure to a wide assortment of drugs, environmental influences, disease, diet, natural hormones, alcohol, tobacco, trauma, and genetic variation, among other factors that contribute to experimental variability. Indeed, differences in gene expression have been observed across donors of human hepatocytes (LeCluyse, 2001;Liguori et al, 2005). Lastly, the sporadic availability and significant cost associated with the use of human hepatocytes must be considered.…”

Therapeutic Applications of Camel’s Milk and Urine against Cancer: Current Development Efforts and Future Perspectives

“…Several drugs have been withdrawn from the market due to the severe adverse effects in patients [24][25][26]. Most of these drugs have shown potential to cause toxicity in healthy organs such as hepatotoxicity and nephrotoxicity [27][28][29]. On the other hand, camel's milk (CM) is an excellent source of wellbalanced nutrients and serves as the main source of food.…”