In addition, the currently available liver chemistries, such as serum alanine aminotransferase (ALT), do not reliably distinguish between mild and transient DILI, which is of no consequence for the patient who can continue to receive the drug safely, versus DILI that will progress to life-threatening injury if drug therapy is not promptly stopped.3 In addition, currently available tests generally cannot distinguish which specific drug is causing the DILI in patients on multiple drug therapy. What is clearly needed are better biomarkers of DILI to help clinicians, as well as provide more meaningful liver safety data in

clinical trials of new drugs. We believe that the peripheral blood (PB) transcriptome may contain information that could address the shortcomings of currently available DILI diagnostic tools. Support for the PB transcriptomic approach comes from several recent findings. In an in-life rat MLN8237 study of eight hepatoxicants, we recently demonstrated that PB cell gene expression can be successfully utilized to detect the presence and severity of toxic responses in the liver.4 In fact, these studies suggested that PB transcriptomic data might be more sensitive to liver injury than traditional clinical tests and therefore able to detect DILI earlier. In addition, the pattern of PB cell transcriptomic response varied across

toxicants, indicating the existence Akt inhibitor of “signatures” that could be useful in identifying the specific drug responsible for DILI. With specific respect to acetaminophen (APAP), the most common identifiable causative agent of acute liver failure in the US, we have shown that in rats treated with toxic doses, PB transcriptomic signatures, particularly in immune and inflammatory pathways, outperform traditional histological or clinical chemistry Selleckchem DAPT markers in detecting DILI. Furthermore, by probing human whole blood transcriptomic data from clinical overdose patients with human

orthologs of this rat PB signature, we were also able to differentiate these patients from nonexposed individuals.5 The hypothesis tested in the current study was that a supratherapeutic but not overtly toxic APAP dose would result in readily detectable changes in the human PB transcriptome and that these changes would be qualitatively similar to changes we have demonstrated in rats and humans after toxic doses of APAP.5 ALT, alanine aminotransferase; APAP, acetaminophen; AUC, area under the curve; CBC, complete blood counts; CYP2E1, cytochrome P4502E1; DEGs, differentially expressed genes; DILI, drug-induced liver injury; GSA, gene set analysis; GSH, glutathione; IPA, ingenuity pathways analysis; NAPQI, N-acetyl-p-benzoquinone-imide; PB, peripheral blood. Subjects were healthy volunteers from 18-55 years old weighing 55 to 85 kg and not taking any over-the-counter or prescription medications.