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Toxicity Research Foundation
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Trovafloxacin, a
quinolone antibiotic, is an idiosyncratic hepatotoxin. Postmarketing
experience in more than 2 million patients uncovered reports of 150
cases of hepatotoxicity including 14 cases of acute liver failure. To
address the mechanism of this adverse effect, Liguori et al. compared
trovafloxacin to four other quinolones. None caused toxicity in animal
models or in cultured human hepatocytes at very high doses. Microarray
analysis of human hepatocytes, however, revealed changes which
distinguished trovafloxacin from the other drugs in this class. A set
of genes indicative of oxidative stress was selectively upregulated.
Trovafloxacin depleted GSH in HepG2 cells at a much lower
concentration than the other quinolones. This was preceded by
increased peroxide exposure (DCF fluorescence). Further analysis
revealed unique regulation of 142 genes, including some involved in
RNA transcription. Since trovafloxacin inhibits bacterial
topoisomerase and mammalian topoisomerase II is essential for
transcription by RNA polymerase II, gene expression changes caused by
trovafloxacin were compared to that caused by the topoisomerase II
inhibitor, etoposide. Similar downregulation of genes involved in RNA
transcription was observed with both drugs. Interestingly, the gene
expression changes were very different in rat hepatocytes, although a
few were the same as in human cells. These studies use a toxicogenomic
strategy to identify changes in gene expression in human hepatocytes
which may provide a unique signature and clues to pathogenesis, even
in the absence of toxicity in the experimental system. Although this
is a logical and meritorious approach in providing plausible candidate
mechanisms contributing to toxicity or to susceptibililty, the
evidence is circumstantial, there were many alterations (which are
important?), and there is a presumption that gene expression changes
are involved in toxicity. Thus, the mechanism of trovafloxacin induced
hepatotoxicity in rare individuals remains unknown. (See HEPATOLOGY
2005;41:177-186.) Hepatology
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