This project investigates how chemical toxins or physical factors alter metabolic processes. NMR methods provide a unique approach for the investigation of metabolic and physiological processes in intact systems, perfused organs, cell suspensions, as well as by examination of cell extracts. Endogenous nitric oxide (NO) modulates many physiological and pathophysiological processes. Nitroglycerin is apparently able to mimic many of the effects of endogenous NO, however the basis for its effects are unclear and remain controversial. In order to evaluate the effects of nitroglycerin on NO production, we are investigating the reaction of NO with the NO-sensitive fluorescent indicator, 4,5-diaminofluorescein (DAF-2) using NMR spectroscopy. Reaction of DAF-2 with NO results in formation of green-fluorescent triazolofluorescein. We are currently collaborating with Ron Mason's group in the immunity, inflammation and disease laboratory to clarify the basis for the physiological effects of nitroglycerin. We recently initiated NMR studies of the effects of metformin, the most widely prescribed drug in the treatment of type 2 diabetes mellitus. The effects of metformin are thought to be mediated both enzymatically and non-enzymatically - as a scavenger of di-carbonyl compounds, several of which, e.g. diacetyl, are known toxicants. Dicarbonyl compounds such as 3-deoxyglucosone are also formed by the Maillard reaction and consequently are increased in Type 2 diabetics. The ability of metformin to scavenge such compounds represents a potential basis for its protective effects. During the last year, we have also worked with a group at the EPA using NMR to identify a previously unknown metabolite derived from the local water supply after chlorination treatment.
