Effects of commonly used drugs on the metabolism of selenium and copper

Project Summary

The life expectancy is increasing constantly, in part based on an improved medical care. On average, every senior in Germany >60 y of age is taking three medications per day, being at risk for developing side-effects due to polypharmacy. Interfering effects of drugs and drug combinations on trace elements (TE) are rarely studied. Taking selenium (Se) as an example, the anti-diabetic drug metformin, aminoglycoside antibiotics or lipid-lowering statins are known to affect selenoprotein biosynthesis. It is however unclear, how these drugs act in combination, and to what extent other TE are also affected. We hypothesize that medication is an important modifier of TE metabolism. As primary focus, effects of commonly used drugs on Se and copper (Cu) metabolism and biosynthesis of the transport proteins selenoprotein P and ceruloplasmin are studied. Their in vitro responses to the commonly used drugs will provide testable hypotheses to be analysed in the cross-sectional EPIC and longitudinal TEhab cohorts. To allow an unbiased overview, a compound library of established and novel drugs will be analysed by high throughput screening. As the molecular mode of action of most of the tested drugs is known, their effects will be studied under TE-rich and TE-poor conditions to identify overlaps in affected pathways and TE deficit-related risks. Highly active TE metabolism disrupting drugs and drug combinations will be characterized in molecular and analytical detail by assessing time- and concentration-dependent molecular signatures and TE fingerprints. Collectively, these analyses will broaden our understanding of drug-TE interactions, identify dangerous TE metabolism interrupting drugs and combinations and elucidate the importance of the TE status for these unknown, potentially adverse and likely unwanted side effects.