Effects of açaí berry (Euterpe oleracea) extracts on human antioxidant systems and drug metabolism
- UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
- Suneel Kumar Kandagatla (Creator)
- Institution
- The University of North Carolina at Greensboro (UNCG )
- Web Site: http://library.uncg.edu/
- Advisor
- Gregory Raner
Abstract: The source and sink of reactive oxygen species are diverse and so are the control mechanisms to counteract them. Sources may be exogenous or endogenous from normal metabolic pathways. Similarly, the sink could be a simple radical scavenging event by small molecule antioxidants and antioxidant enzymes or complex events involving cellular signaling processes. The effects of reactive oxygen species may precipitate cellular dysfunction from its toxicity, protect from invading microorganisms or perform essential functions through regulation of cell signaling pathways. Excessive Reactive oxygen species leads to oxidative stress which mediates cellular damage and is implicated in several pathological conditions. The current research addresses biological systems that may effect redox balance in humans. One goal of the current research was to establish structure activity relationship for substrate binding to several human drug metabolizing enzymes implicated in reactive oxygen species generation, namely CYP2A6 and CYP2E1. The substrate dynamics of these two enzymes were studied by probing the active site with a series of small chain saturated and 2,3-unsaturated aldehydes using human liver microsomes. The study demonstrated that the aldehydes inhibited both the enzymes in competitive manner with unsaturated aldehydes being more potent than their saturated counterparts. The potential for p-stacking interactions between the phenylalanine rich active site of these enzymes and the double bond at 2-position in unsaturated aldehydes conferred high affinity for these aldehydes. It also confirmed an earlier findings that the active site of CYP2A6 is rigid where as CYP2E1 is flexible due to the presence of extended p-system allowing the expansion of its active site. Another goal was to examine the possible interactions between human cytochrome P450 enzymes of pharmacological and toxicological importance with a natural product called açaí. Açaí (Euterpe oleracea) is a Brazilian palm tree that has emerged from traditional medicinal plant to a recent super-fruit status. The assumption that it is safe to consume açaí currently lacks evidence from its interactions with drug metabolizing cytochrome P450 enzymes. The interaction between the crude extracts of açaí and major cytochrome P450 enzymes involved in drug metabolism and toxicology demonstrated the potential for chloroform extract to inhibit the isoforms CYP1A1, CYP2B6 and CYP2C8. The Michaelis-Menten Kinetics studies indicated mixed mode of inhibition of these enzymes by crude chloroform extract of açaí with low KI and KI’ values for CYP2C8 followed by CYP2B6 and CYP1A1. In addition, the study was extended to identification of inhibitors for toxicologically important CYP2A6 and CYP2E1 using a collaborative bioassay-guided fractionation approach. Although the crude chloroform extract of açaí showed considerable inhibition of these enzymes, specific inhibitors were not identified. Finally, the regulation of a signal transduction pathway namely Nrf2/ARE signaling pathway by açaí constituents was also studied as a potential strategy to prevent oxidative damage. The nuclear factor erythoid 2-related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is a cellular defense to counteract oxidative stress. Activation of this pathway increases the expression of a battery of antioxidant genes. This was achieved by monitoring the activation of a cis¬-acting DNA sequence referred to as Antioxidant Response Element (ARE) contained in a luciferase-containing promoter vector in cultured HepG2 cells. A high-throughput analysis of fractions generated using bioassay-guided fractionation of açaí has resulted in the identification of a class of compounds known as Pheophorbides as the inducers of ARE-luciferase. Dose response analysis using pure compounds demonstrated significant induction of ARE-luciferase at concentrations as low as 8.2 µM and 16.9µM for Pheophorbide a methyl ester and Pheophorbide a, respectively.
Effects of açaí berry (Euterpe oleracea) extracts on human antioxidant systems and drug metabolism
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Created on 8/1/2015
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Additional Information
- Publication
- Dissertation
- Language: English
- Date: 2015
- Keywords
- Açaí berry, Euterpe oleracea, Aldehydes, Antioxidants, Antioxidant Response Element, Luciferase plasmid vector, Cytochrome P450 enzymes, Inhibition, Nrf2/ARE signaling pathway, Induction, Oxidative stress, Reactive oxygen species
- Subjects
- Ac¸ai´ palm $x Metabolism
- Antioxidants $x Physiological effect
- Active oxygen in the body
- Oxidation, Physiological
- Oxidative stress
- Cytochrome P-450