Project Details
Projekt
Interaction between metabolism and transport of toxicological-relevant substances in the gastrointestinal barrier
Subject Area
Public Health, Healthcare Research, Social and Occupational Medicine
Term
from 2005 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 5442059
Polycyclic aromatic hydrocarbons (PAH) comprise a large group of ubiquitously occurring environmental contaminants with the pro-carcinogen benzo[a]pyrene (BP) as best studied representative. The main source of PAH uptake for non-smokers is the daily diet. PAH are only formed in significant amounts during processing (heating and drying) and preparation (e.g. smoking and grilling) of fatty foods such as meat, fish and vegetable oils and fats. In the first period of this project BP its detoxication and hepatobiliary excretion was studied in transporter knockout mice investigating the lack of the two ABC-transporters Breast Cancer Resistance Protein (Bcrp/Abcg2) and Multidrug Resistance-associated Protein 2 (Mrp2/Abcc2). The data showed an important role of these two transporters for BP excretion from the body. Additionally we could show in an in vivo study that a food component, the prominent flavonoid Quercetin, strongly increases the hepatobiliary excretion of BP from the body.However, in reality a mono-exposure of humans with BP alone never occurs: always mixtures of PAH are taken up by nutrition. These mixtures consist partly of carcinogenic compounds such as BP, but in percentage terms in substantial proportions of non-carcinogenic PAH such as pyrene and fluoranthene. However, the influence of such mixtures of non-carcinogenic and carcinogenic PAHs on the molecular mechanisms is still inadequately investigated and understood. Accordingly, this project is aimed to investigate the impact of such real PAH mixtures on the metabolism, receptor activity and the genotoxicity of BP based on the results of the last funding period. Important endpoints comprise changes of the metabolism of BP by detection of characteristic metabolites involved in bioactivation or detoxification (DNA adducts, analysis of metabolite profile), the induction of gene expression and nuclear receptor pathways associated with the metabolism and finally, the in vivo verification of the in vitro data using humanized receptor mouse models.The results of this project are expected to contribute to a better understanding of molecular effects of real human PAH exposure in contrast to the often well-characterized single exposure and in turn allowing a better assessment of the carcinogenic potential of BP and the associated risk to humans.
DFG Programme
Research Grants
Co-Investigator
Dr. Stefanie Hessel
