Bioactivation and binding of polycyclic aromatic hydrocarbons in blood vessel endothelia
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants formed by incomplete combustion of organic materials such as fossil fuels and wood. Experimental and epidemiological studies indicate that PAHs may be involved in the development of cardiovascular disease.
In vivo and in vitro studies were carried out to examine whether blood vessel endothelia are potential targets for PAH toxicity in mammals and birds. Tissues and cells that are sites for irreversible binding of benzo(a)pyrene (B(a)P) and 7,12-dimethylbenz(a)anthracene (DMBA), were identified in mice, rats and chicken embryos, using autoradiographic techniques. Binding of DMBA and the heterocyclic amine 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) was examined in cultured human umbilical vein and artery endothelial cells (HUVEC and HUAEC). Enzyme inducers and inhibitors were used to elucidate involvement of cytochrome P4501A (CYP1A) in local metabolite binding. Furthermore, the CYP1A-related enzyme activities 7-ethoxyresorufin 0-deethylase (EROD) and DMBA hydroxylase were determined in the tissues.
In animals exposed to a CYP1A-inducer (3,3',4,4',5-pentachlorobiphenyl or β -naphthoflavone), irreversible B(a)P and DMBA binding was observed in endothelial cells in certain arteries, veins and capillary networks. There was no significant binding in endothelia from control animals. CYP1A- induction also increased DMBA and Trp-P-1 binding in HUVEC, but not in HUAEC. The formation of bound metabolites in endothelial cells generally correlated with induction of EROD and DNMA hydroxylase.
In conclusion, PAHs can be metabolically activated in blood vessel endothelia in several organs, including heart, lung and brain, in rodents and chicken embryos as well as in cultured HUVEC. The results imply endothelial cells as targets for chemical toxicity, although different endothelia exhibit major differences in bioactivation ability.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2001. , 44 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 597
Developmental biology, Polycyclic aromatic hydrocarbon, PAH, endothelial cells
Research subject Ecotoxicology
IdentifiersURN: urn:nbn:se:uu:diva-572ISBN: 91-554-4907-7OAI: oai:DiVA.org:uu-572DiVA: diva2:166068
2001-01-24, Lindahlsalen vid EBC, Norbyv. 18A, Uppsala, 09:30