Biomarkers for toxicity during chronic or acute exposure. The urinary excretion of degradation products of cellular macromolecules as markers forcytotoxicity (LBI2822)

Biomarkers for toxicity are essential to assess whether humans (workers in industry, agriculture, etc.) are exposed to levels of toxicants that affect their health. For many practical purposes, such biomarkers should be rather non-specific so as to allow the detection of damage by a high percentage of potential toxicants. In some cases, however, highly specific biomarkers for toxicity in a single organ only are needed. For that purpose, biomarkers of a specific or an organ-specific nature are needed. Ideally, such biomarkers should be non-invasive, i.e. assayable in urine samples, because that facilitates monitoring of larger groups continuously, as might be desirable in industries or certain environments.
lt has been well established that radical formation is the underlying process in many pathological and toxicological processes. This may lead to lipid peroxidation and oxidative damage to nucleic acids or proteins. In this project we intend to investigate whether the extent and type of cell damage can be characterized by measuring urinary excretion of breakdown products of these modified cell constituents.
Apart from measuring biomarkers of early effects, we will also concentratie on biomarkers of late effects (i.e. necrosis). Modified amino acids (tyrosine-O-sulphate and hydroxyproline) derived from the breakdown of proteins and excreted in urine might be suitable candidates for this. We will validate the potential biomarkers by measuring the excretion of the various compounds in urine of animals exposed to toxic compounds (and for which pathological data are availabie), and of patients treated with cytostatic drugs and undergoing radiotherapy.
Due to the anticipated co-operation between our two instituties and collaboration with three industrial toxicology groups, we will be abie to measure a relatively large number of urinary biomarkers in animal species and in humans. Moreover, we will also be able to correlate the urinary biomarkers with each other and, in animals, with pathological data.

Een aantal nieuwe, specifieke en zeer gevoelige analytische methoden zijn ontwikkeld voor een aantal potentiële urinaire biomarkers. Met behulp van deze methoden werden urinemonsters onderzocht van proefdieren die aan specifieke, radicaalschade veroorzakende, toxische stoffen waren blootgesteld. Op non-invasieve wijze kunnen schadelijke effecten van specifieke geneesmiddelen (bijvoorbeeld cytostatica) of andere chemische verbindingen of mogelijk zelfs UV-straling worden gemeten. 

Unilever was bereid een vervolg(aio-)project te financieren om effecten van radicaalschade en van anti-oxidantia in relatie tot voedingsmiddelen te onderzoeken.

Vier bedrijven en één universiteit zij bij dit project betrokken.

Dr. J.H.N. Meerman
Universiteit Leiden
Afdeling Toxicologie
Sylvius Laboratorium
Postbus 9503
2300 RA LEIDEN.