Reactive Oxidation Species and Antioxidants Flashcards
What antioxidant does the lens use to combat oxidative stress
Enzymes glutathione reductase, GSH-Px, catalase, and SOD
What vision threatening diseases are associated with oxidative stress
cataract, glaucoma, diabetic retinopathy, and age-related macular degeneration
What study confirmed the role of antioxidants in slowing progression of AMD
AREDS- Age-Related Eye Disease Study
What is the function of ROS under normal physiologic conditions
reactive oxygen species (ROS) participate in normal biochemical processes, where they either act as intermediaries or function as second messengers. Also, ROS can be generated by exogenous influences, such as exposure to ultraviolet (UV) light or cigarette smoking. Oxidative stress occurs when the production of ROS exceeds their degradation
How are ROS generated
from metabolic processes, inflammatory responses, and exposure to UV light
Examples of ROS
hydrogen peroxide (H2O2) and singlet oxygen (1O2), as well as lipid peroxides and reactive carbohydrates such as ketoamine and ketoaldehyde groups. Free radicals, another group of ROS, possess an unpaired electron that makes them highly reactive toward other molecular species
What are exogenous sources of ROS
UV light and tobacco smoke
What are endogenous sources of ROS
electron transport chain in mitochondria and, as part of our innate immune response by neutrophils and macrophages, respiratory burst, where superoxide anion (O −) 2 and the hydroxyl radical (OH) form to attack pathogens. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox) constitute an enzyme family that functions primarily to produce ROS and is expressed in many cells
How does ROS lead to cell death
Apoptosis. Can also occur through loss of the barrier function of the plasma membrane via a process known as lipid peroxidation
What pathways are involved in eliminating ROS
1) glutathione peroxidase; (2) catalase; and (3) peroxidase
ROS- Superoxide anion (O2-). What is the source and antioxidants involved in detoxification
Source: electron transport chain (mitochondria), respiratory burst (neutrophils), xanthine oxidase
Antioxidants: Superoxide dismutase (SOD)
ROS- Hydroxyl radical (OH.). What is the source and antioxidants involved in detoxification
Source: electron transport chain (mitochondria), respiratory burst (neutrophils)
Antioxidants: Catalase and peroxidase
ROS- hydrogen peroxide (h2O2). What is the source and antioxidants involved in detoxification
Source: electron transport chain (mitochondria), respiratory burst (neutrophils), superoxide dismutase
Antioxidants: Catalase and Peroxidas, glutathione peroxidase
ROS- Singlet oxygen (1O2). What is the source and antioxidants involved in detoxification
Source: Photo-oxidation
Antioxidants: Carotenoids (quenching)
How does lipid peroxidation occur
3 steps- initiation, propagation and termination.
Initiation- fatty acids converted to intermediate radical due to loss of one hydrogen. This reacts with oxygen to form peroxidase radical. ROO. This is called lipid peroxidation
Example of free radical scavenger
Vitamin E
How can photooxidation be inhibited
O2 quenching carotenoids
What structures can lipid peroxidation damage
Retina and Lens
Defense mechanism from ROS
UV light exposure protection by cornea and lens. High ascorbate (vitamin C) content of the aqueous and vitreous. Enzymes which neutralise ROS eg Superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase
What is the mechanism of damage in siderosis bulbi and haemosiderosis bulbi
Formation of h2O2 by free iron (Fe2+) is the mechanism underlying damage to structures in the eye in siderosis bulbi and hemosiderosis bulbi. the former is due to iron released into the eye from a retained intraocular foreign body; the latter, from the breakdown of hemoglobin molecules in cases of intraocular hemorrhage. In both conditions, excess Fe2+ can accumulate in the trabecular meshwork, neurosensory retina, and retinal pigment epithelium (RPE), leading to secondary dysfunction
How is most UVB radiation absorbed in the eye
(<320-nm wavelength) striking the human eye is absorbed either by the cornea or by the ascorbate present at high levels in the aqueous humor, a certain amount reaches the lens epithelium, where it can cause damage. UVA light (320–400-nm wavelength) can penetrate more deeply into the lens, where it can react with various chromophores to generate H O , O *−, and 1O .
What is the purpose of sulfhydryl groups in the lens
The lens contains unusually high levels of protein sulfhydryl groups that must exist almost entirely in the reduced state for the tissue to remain transparent
Which antioxidant in the lens acts as a major scavenger of ROS
Glutathione (GSH), concentrated at the lens epithelium. Studies have indicated that a cortical–nuclear barrier may exist in the mature human lens, which inhibits the free flow of GSH to the nucleus. As a result, the human lens nucleus becomes more susceptible to oxidative damage and cataract formation with age.
What did the AREDS, AREDS2 and VECAT trial show with regards to cataracts
found that high-dose formulations of antioxidants neither prevented the development nor slowed the progression of age-related cataracts.
Impact on retinal photoreceptors when exposed to oxidative challenges
Experimental data have shown that retinal photoreceptors degenerate when exposed to oxidative challenges such as hyperbaric oxygen, iron overload, or injection of lipid peroxide into the vitreous humor. In addition, the retina degenerates when antioxidant defenses are reduced
Characteristics of the retina increasing its susceptibility to damage from lipid peroxidation
1) Vertebrate rod outer segments susceptible due to high levels of PUFA’s. Phospholipids contain docosahexaenoic acid, highly polyunsaturated
2) Rod inner segments rich in mitochondria. Majority of endogenous ROS produced by mitochondrial electron transport chain leaking activates ROS
3) Abundant oxygen supply in choroid and retina vessels increases risk of oxygen damage
4) Many chromophores in outer retina. Light exposure may trigger photo oxidative processes mediated by 1O2
What antioxidants are found in vertebrate retinas and RPE
1) Selenium
2) GSH
3) Selenium dependent GSH-Px
4) Non selenium dependent GSH-Px (glutathione S transferase)
5) Vitamin E
6) SOD
7) Catalase
8) Carotenoids
Where is the highest concentration of selenium in the human eye found
RPE. Levels in retina remain constant but increase with age in RPE
What does superoxide dismutase SOD do?
Catalyzes the dismutation of superoxide to H2O2 which is further reduced to water by catalase or peroxidase
What is the precursor of vitamin A
Beta carotene
What makes up the yellow pigment at the macula
Studies of postmortem human retinas have shown that carotenoids make up the yellow pigment in the macula. Two carotenoids, lutein and zeaxanthin, are present in the macula and located in the Henle fiber layer
Where is zeaxanthin and lutein mainly found
In humans, zeaxanthin is concentrated primarily in the fovea, whereas lutein is dispersed throughout the retina
Where are carotenoids found in the eye
Carotenoids are present only in the retina and are absent from the RPE. In the peripheral retina, lutein and zeaxanthin are concentrated in rod outer segments and may act as antioxidants to protect against short- wavelength visible light
Where are vitamin E and selenium primary found
RPE
Which metabolic pathways are implicated in the development of diabetic retinopathy
- polyol pathway
- protein kinase C (PKC) pathway
- hexosamine pathway
What risk factors related to oxidative mechanisms are found in AMD
sunlight exposure, smoking, and to some extent genetics
What did the AREDS and AREDS2 trial show with regards to antioxidants and their role in AMD
both trials supported the role of antioxidants in limiting the progression of AMD in high-risk patients
