Arthur G. Zupko Institute for Systems Pharmacology and Pharmacogenomics
Arthur G. Zupko’s Institute of Systems Pharmacology and Pharmacogenomics is housed in a newly built and equipped laboratory that currently performs metabolomics research. Mass spectrometry is employed to conduct metabolomics investigations into the causation, prevention and treatment of human diseases through the discovery and quantitation of biomarkers. Such studies generally lead to an enhanced understanding of the pathobiology of disease. We have a number of active projects related to various liver diseases, leukemia, lung cancer and multiple sclerosis, together with disease prevention through dietary manipulation with collaborators from US and European universities and from the US National Cancer Institute, NIH. We plan to increase our outreach to other diseases using our expertise in metabolism and the application of mass spectrometry-based metabolomics. The laboratory has now started to train pharmacy students within its research program.
This paper is an advance in our understanding of liver cirrhosis, a disease that kills over 1.3 million persons per annum (35,000 deaths in the US; 9th leading cause of death). Understanding the severity of cirrhosis is key to treatment. So-called decompensated cirrhosis is an end-stage disease for which the only intervention is liver transplantation, which is offered to less than 10% of patients due to the shortage of donor livers.
The findings that fetal bile acids, normally absent in adults, reach increasingly high levels in plasma as the disease progresses adds not only an important biomarker for evaluation of the stage of cirrhosis but also provides mechanistic insights that parallel inborn errors of bile acid metabolism in neonates and young children.
Oncometabolites are produced by cancer cells and assist the cancer to proliferate and progress. Oncometabolites occur as a result of mutated enzymes in the tumor tissue or due to hypoxia. These processes result in either the abnormal buildup of a normal metabolite or the accumulation of an unusual metabolite. Definition of the metabolic changes that occur due to these processes has been accomplished using metabolomics, which mainly uses mass spectrometry platforms to define the content of small metabolites that occur in cells, tissues, organs and organisms. The four classical oncometabolites are fumarate, succinate, (2R)-hydroxyglutarate and (2S)-hydroxyglutarate, which operate by inhibiting 2-oxoglutarate-dependent enzyme reactions that principally regulate gene expression and response to hypoxia. Metabolomics has also revealed several putative oncometabolites that include lactate, kynurenine, methylglyoxal, sarcosine, glycine, hypotaurine and (2R,3S)-dihydroxybutanoate. Metabolomics will continue to be critical for understanding the metabolic rewiring involving oncometabolite production that underpins many cancer phenotypes.
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