Hepatotoxicity and the Circadian Clock: A Timely Matter

In compliance with the societal demand to reduce and ultimately ban animal-based toxicity tests for chemical hazard identification and risk assessment, large-scale efforts are being undertaken to develop validated in vitro assays on the basis of risk profiles of 'omics-based biomarkers. Evidence is increasing that uptake, metabolism, and detoxification of chemicals is under control of the circadian clock and that, accordingly, the severity of toxic responses can depend on the time of day of exposure (chronotoxicity). Nonetheless, the involvement of the circadian clock in modulating toxicity is largely neglected. Here, focusing on the liver, we discuss the intimate link between the circadian clock and drug metabolism, detoxification, and other toxicity-related biological processes, as well as its impact on the outcome of in vivo and in vitro transcriptomics experiments. Moreover, we present a conceptually novel approach for toxicity/toxicogenomics assays that is not only expected to improve sensitivity and specificity, but will also provide insight into chronotoxic properties of chemicals.

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