Oxygen Metabolism and Human Disease

Oxidative damage has been implicated in as many as one hundred disease states, including cardiovascular disease, cancer, stroke, neurodegenerative diseases, and chronic inflammatory diseases. The health-promoting effects of diets rich in fresh fruits and vegetables probably result in large part from their high content of antioxidant compounds, particularly vitamin C and vitamin E.

Generation of altered, oxidized bases in DNA, such as 8-oxoguanine or 5-hydroxyuracil, and thymine glycol (see here also) is intensely mutagenic. The intracellular generation of reactive oxygen species causes the formation of DNA bases such as 8-oxoguanine (8-hydroxyguanine) or thymine glycol. 8-oxoguanine is the most significant product of oxidative DNA damage. One of the protective mechanisms is not a DNA repair enzyme, but a nucleotide hydrolase. In E. coli, 8-oxo-dGTP accumulates in oxygen-stressed cells, and an enzyme encoded by the mutT gene cleaves this altered nucleotide before it can be used as a DNA replication substrate:

8-Oxo-dGTP + H 2 O ---> 8-Oxo-dGMP + PPi

A similar enzyme exists in mammalian cells.

Partly because cancer incidence is strongly correlated with age, many scientists also attribute normal aging to the accumulation of unrepaired mutagenic DNA lesions, and oxidative stress is implicated in what has been called the "free radical theory of aging."

Human mutations in the gene encoding the copper/zinc form of superoxide dismutase have been shown to cause amyotrophic lateral sclerosis, a neurodegenerative disorder better known as Lou Gehrig's disease.

The role of peroxynitrite in the nerve degeneration causing multiple sclerosis (MS) has been brought into focus with the observation that patients with gout hardly ever develop MS, suggesting that the chronic uric acid elevation causing gout also prevents the development of MS.

Mutations affecting the mitochondrially encoded subunits of cytochrome oxidase have been associated with Alzheimer's disease.

See also: Reactive Oxygen, Antioxidants, Types and Consequences of DNA Damage (from Chapter 25), Uric Acid