To understand toxicity mechanisms in order to help rational risk assessment process and to develop mechanism-based in vitro bioassays for biomonitoring.
Identification of genes and transacting factors that respond to oxidative stress. Understand the mechanistic link between DNA damage, transcriptional arrest and upregulation of P53. Investigate the causal link between downregulation of the CYP2E1 gene and certain mental disorders.
- Mechanistic toxicology at Entox needs to be strengthened for two main reasons:
- Understanding toxicity mechanisms is one essential part of rational and reliable risk assessment process and
- mechanistic studies provide the necessary know how for the development of cell based and in vitro bioassays for determining different types of toxic responses.
- Our long term objectives address some of the key questions in this area:
- what are the defence mechanisms and signalling pathways in cells that are activated during oxidative stress?
- what is the mechanism of upregulation of the P53 protein by genotoxic agents, chromosomal damage and/transcriptional arrest?
- what is the biological significance and toxicological consequences of downregulation of the toxin metabolizing CYP2E1 during mental disorders?
- The knowledge obtained from these projects is used to develop improved recombinant gene vectors for better prediction and understanding the type of toxicity elicited by environmental chemicals.
Major progress was made in understanding how Bilirubin (BR) is used by the cells as a protecting agent against oxidative stress.
We have obtained evidence for the mechanisms that regulate BR homeostasis and sub cellular distribution in cells during and after an oxidative stress insult. Appearance of oxidated BR metabolites in urine are suggested as biomarkers for oxidative stress conditions of the body.