Tienilic acid (TA) was withdrawn due to idiosyncratic hepatotoxicity. Two hypotheses for the mechanisms of idiosyncratic reactions are the
hapten and danger hypotheses, which are not mutually exclusive. Both human CYP 2C9 and rat CYP 2C11 metabolize TA to a reactive metabolite that was reported to bind exclusively to these
enzymes. TA-Induced liver toxicity is associated with
antibodies against CYP 2C9, thus TA appears to act as a
hapten. However, if the binding were limited to CYP 2C, it is unlikely that this would lead to significant cell stress. If TA does not cause cell stress it would suggest that acting as a
hapten is sufficient to induce an idiosyncratic reaction. To test whether TA can cause cell stress rats were dosed with TA and hepatic gene expression was profiled at 6 and 24 hr after
drug administration. TA induced changes in genes involved in oxidative stress (
aldo-keto reductase,
glutathione-S-transferase,
thioredoxin reductase,
epoxide hydrolase),
inflammation (IL-1beta,
interferon regulatory factor 1,
macrophage stimulating protein 1), cytotoxicity (caspase-12), and liver regeneration (p27(Kip1), DUSP6,
serine dehyratase,
spectrin beta II,
inhibin beta(A)). These data support the hypothesis that danger signals in the form of cell-stress may be involved in initiating the immune response observed in TA-induced toxicity. In separate experiments, we examined the changes in gene expression induced in mice by
sulfamethoxazole, which also causes idiosyncratic reactions.
Sulfamethoxazole is an aromatic
amine, and aromatic
amines in general are associated with idiosyncratic
drug reactions. They form reactive metabolites that both act as electrophiles and can redox cycle; therefore, it was assumed that
sulfamethoxazole would cause some type of cell stress, the only question was what changes in
mRNA expression would occur. In contrast to expectations, no changes induced by
sulfamethoxazole could easily be interpreted as a danger signal. These data are presented together because they are the opposite of the expected results and convey a complex story.