“This review provides a chemical foundation upon which the biological community can see how the lesions form that are likely the drivers of disease origin and development.”

8-Oxoguanine (more formally, 7,8-dihydro-8-oxoguanine), directly or indirectly, could be the cause of the second-most-frequent spontaneous mutation, the G to T transversion. Moreover, conditions such as inflammation causes a huge boost in the extent of formation of this DNA lesion, and its further oxidation products (called hyper-oxidized guanines). It is becoming increasingly clear that guanine oxidation is at the root of many diseases.

It recently has been discovered that these hyper-oxidation products of guanine (e.g., spirohydantoins and many other species) exist in living things and may be even more important than the class prototype, 8-oxoguanine. Will Neeley and I decided to write this critical review as a resource for the biological community because the chemistry of guanine oxidation has been difficult to grasp.

Life in an oxygen-rich environment has its advantages, as we use oxygen to do a controlled burn of reduced organic materials to generate the metabolic energy for life. However, when oxidation goes amiss, reactive oxygen and nitrogen species can cause damage to our genome, resulting in precursors to mutations that can give rise to cancer and other genetic diseases and even contribute to aging. This review provides a chemical foundation upon which the biological community can see how the lesions form that are likely the drivers of disease origin and development.

As a student, I studied a chemical toxin found in rice, peanuts and corn that are contaminated with a fungus. The toxin is called aflatoxin B1. It was my job to work out the mechanism of action of this toxin, which causes approximately 400,000 liver cancer deaths per year. After my studies, it was found that a virus, hepatitis B, enhances the carcinogenicity of aflatoxin by up to two orders of magnitude. It is still unknown how the virus and toxin collaborate to cause disease, but one mechanism on the drawing board is that the virus creates inflammation that helps drive certain steps in the multi-step pathway by which normal liver cells are converted to fully malignant cancer cells. I thus became interested in inflammation and its underlying chemistry.

If specific DNA lesions associated with inflammation and other forms of oxidative stress are pinpointed conclusively as the molecular culprits responsible for disease, we can use measurement of those lesions—we call them "biomarkers"—as a way to predict risk. Moreover, maybe we can find (dietary) agents in the environment that will induce biochemical pathways that would make these biomarkers change their values in a direction that would predict lower disease incidence.

Having good biomarkers is of central importance to developing scientifically sound methods of disease prevention. So, the work in the immediate future is to determine which of the many guanine oxidation products are lethal, are mutagenic, or cause other kinds of deleterious biological effects. Those lesions will become the biomarkers used to change behavior in order to prevent disease caused by oxiative stress.

It is cheaper to prevent a disease such as cancer than to treat it. It has been conclusively demonstrated that inducing antioxidant pathways, such as that controlled by Nrf2, reduces the risk to certain types of cancer. We invest heavily in chemoprevention against cardiovascular disease. We should invest more heavily in chemoprevention against cancer.