Predictive Toxicity

Design:

Male Sprague-Dawley rats of approximately 5 weeks and weight range 100-124g were assigned to 4 dose-groups (0, 100, 600 and 1200 mg/kg/day), each comprising n=15. The animals were orally dosed daily using an acetaminophen suspension.

Study:

RNA samples were hybridised to Affymetrix Rat 230 2.0 whole rat genome arrays. Samples were normalised using RMA (robust multi-chip average). Pairwise comparisons were undertaken on linear model fitted data, using empirical Bayesian approaches, with correction for multiple testing. Treated samples were normalised by comparison with timed control samples. Measures of differential expression were obtained through comparisons within a given timepoint and/or drug concentration series.

Conclusions

A clear systematic cellular response was observed that was dose- and time-dependent, most notably at the early timepoint (24 hrs). Functionally, pathways associated with cellular damage and immune activation processes were up-regulated.

Implications

Markers of a hepatic toxic response can be measured in the blood after 24-72 hours, enabling a rapid non-invasive diagnosis to be undertaken.