Toxin Control from Dietary Metals

We are constantly exposed to toxins resulting from the combustion of organic matter.  Cooked food and tobacco smoke contain damaging levels of chemicals such as nitrosamines and polycyclic aromatic hydrocarbons (PAHs).  The toxicity of these compounds is a result of enzymatic activation into potent alkylating agents.  These electrophilic alkylating metabolites react with nucleophiles of deoxyribonucleic acid (DNA) to yield genomic damage.       

Metabolism of nitrosamines and polycyclic aromatic hydroarbons yields DNA alkylation damage.

One way to prevent the onset of cancer is by increasing dietary intake of certain inorganic compounds.  The cancer preventing properties of selenium have been well documented in humans and rats.  Similar rat studies have shown vanadium compounds also prevent cancers induced by alkylating toxins.  The excitement surrounding cancer prevention strategies based upon inorganic compounds is illustrated by an ongoing Phase III trial.  The effects of increased dietary selenium and/or vitamin E on prostate cancer incidence are being studied in over 30,000 men.  Despite the promise of preventing cancer with dietary inorganics, no significant mechanistic data are available to explain the activity.             

X-ray crystal structure of the (V3O9)3- anion.

The aqueous chemistry of selenium and vanadium is dominated by anionic oxo species such as (SeO4)2- and (H2VO4).  Although the reactivity of such anions is largely unknown, we expect these compounds to exhibit appreciable nucleophilicity, owing to the high negative charge density.   We are studying a “toxin interception” mechanism of cancer prevention.  Anionic oxo species of vanadium and selenium may react with electrophilic carcinogens.  The toxin is thus consumed, thereby preventing DNA alkylation damage, mutations, and cancerous growth. 

Crystal of (Bu4N)3 (V3O9) next to a dime for perspective.

We are studying this means of preventing DNA damage at three levels:  model chemical interactions, biochemical studies, and in cellular studies.  Inorganic reactions between metal oxo compounds and carcinogens show us what type of processes may occur in cells.  Biochemical assays demonstrate the influence of metal complexes upon DNA damage.  Finally, cells are grown in media containing different levels of inorganics and then subjected to toxin assaults.  Insights gained from these studies are being used to design second-generation compounds to detoxify carcinogens.  This work is being carried out in an attempt to develop new approaches to preventing cancer. 

Anionic metal oxo species may react with alkylating toxins, thereby preventing DNA damage.

We thank the Cancer Research and Prevention Foundation for generous support of this project.