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Regulation of cytochrome P450 2A6 and phase II enzymes by unsaturated aldehydes

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Todd Steven Mack (Creator)
Institution
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Advisor
Gregory M. Raner

Abstract: Human Phase I and Phase II drug metabolizing enzymes are known to interact with foreign chemicals that enter the body as a defense mechanism, however, it is often the case that unwanted interactions can occur. Phase I metabolism may form reactive electrophiles that can covalently modify DNA, proteins and lipids. These modified electrophilic biomolecules are thought to cause progression of many diseases such as Parkinson’s and Alzheimer’s Disease (3). On the other hand, Phase II enzymes can remove the toxic compounds of the Phase I enzymes. The Phase II enzymes are likely induced via biochemical pathway involving the nuclear transcription factor Nrf2 (4). This current study was designed to probe specific interactions between commonly used essential oils, along with their major aldehyde constituents, and CYP2A6. The overall goal was to gain a better understanding of factors that may govern the inhibitory effects of aldehydes on this isoform. In addition, the ability of the essential oil of Cassia and it’s primary constituent, cinnamaldehyde on Phase II gene induction was probed as well using cultured human hepatoma cells (HepG2). Here the goal was to gain a better understanding of the relationship between oxidative stress, and aldehydes that may be present in commonly used products. The results demonstrated that relatively small unsaturated aldehydes (6-8 carbons) showed a dramatic decrease in the CYP2A6 activity when catalyzing the coumarin 7-hydroxylation reaction. This inhibition could translate to a net antioxidant effect, by preventing the formation of reactive oxygen species (ROS), particularly in the presence of 2A6-activated nitrosamines, which can be carcinogenic. It was also shown that Cassia and cinnamaldehyde had an inductive effect on Phase II enzymes in human hepatoma cells, such as heme oxygenase 1 (HO1) and epoxide hydrolase (EPHX), thus exerting a net anti-oxidant effect on the cells as a whole.

Additional Information

Publication
Thesis
Language: English
Date: 2009
Keywords
Aldehydes, Cassia, Cinnamaldehyde, Hepatoma cells
Subjects
Enzymes $x Metabolism.
Aldehydes.
Cytochrome P-450.
Antioxidants.
Oxygenases.
Essences and essential oils $x Physiological aspects.