Sphingolipid metabolism as a marker of hepatotoxicity in drug-induced liver injury

Drug-induced liver injury (DILI) has a substantial impact on human health and is a major monetary burden on the drug development process. Presently, there is a lack of robust and analytically validated markers for predicting and early diagnosis of DILI. Sphingolipid metabolism and subsequent disruption of sphingolipid homeostasis has been documented to play a key role contributing to hepatocellular death and subsequent liver injury. A more comprehensive understanding of sphingolipid metabolism in response to liver toxicity has great potential to gain mechanistic insight into hepatotoxicity and define molecular markers that are responsible for hepatocyte dysfunction. Here, we present an analytical platform that provides multidimensional mass spectrometry-based datasets for comprehensive structure characterization of sphingolipids extracted from human primary hepatocytes (HPH) exposed to toxic levels of acetaminophen (APAP). Sphingolipid metabolism as measured by characterization of individual sphingolipid structure was sensitive to APAP toxicity displaying a concentration-dependent response. A number of sphingolipid structures were differentially expressed across varying APAP exposures highlighting the unique role sphingolipid metabolism has in response to hepatotoxicity and its potential use as a molecular marker in DILI.