San Diego, April 10 -- Naturally occurring genetic variations in drug metabolizing enzymes significantly contribute to whether a person develops certain cancers, according to recent studies by University of Pittsburgh investigators who are presenting their findings at the annual meeting of the American Association for Cancer Research.
These enzymes, called cytochrome P450s (CYPs) and phase II enzymes, normally metabolize, or breakdown, chemicals entering the body. Slight variations in the gene for a given enzyme result in different forms of that enzyme, each form performing the same function but at a different rate. Because of these genetic differences, individuals metabolize foreign substances differently from one another.
"Individuals with certain genetic profiles or a history of certain environmental exposures are strongly at risk for head and neck cancer," said Marjorie Romkes, Ph.D., assistant professor of environmental and occupational health and toxicology. Elevated activity of one enzyme (CYP2E1), low activity of another (CYP2C19), smoking, alcohol consumption and occupational exposures independently place individuals at increased risk for head and neck cancer, according to preliminary findings comparing 40 head and neck cancer patients with 85 cancer-free controls.
"Certain enzyme genotypes in people without cancer appear to be associated with DNA damage that could lead to cancer," said Dr. Romkes in regard to another presentation showing that normal human cells with certain enzyme forms showed higher levels of DNA mutations than human cells with different enzyme forms.
Another ongoing collaborative research project with Phouthone Keohavong, Ph.D., indicates that individuals with bladder cancer who had p53 mutations either had a history of exposure to a cancer-causing substance or abnormalities in enzymes that process environmental chemicals. p53 is a gene that normally suppresses tumor growth. When mutated, the p53 gene cannot function correctly and cancer arises. p53 mutations are suspected to be involved in about half of all cancers.
Some CYPs remove cancer-causing agents by turning them into benign chemicals within the body. Researchers aim to develop drugs that would accelerate the activity of these enzymes in patients whose enzymes naturally work very slowly. Other CYPs do the reverse, taking procarcinogens (potentially cancer-causing substances) and turning them into cancer-causing chemicals that linger in the body where they can cause damage. The Pitt investigators are working with drugs to block or slow the activity of these enzymes in individuals who have enzymes that rapidly produce such cancer-causing substances.
Other collaborators on these studies include Robert Branch, M.D.; Adedayo Adedoyin, Ph.D.; Cheri White; Regie Frye, Ph.D.; Jonas Johnson, M.D.; David Eibling, M.D.; Barb Henry; Gilberto Fregoso, M.D.; William L. Bigbee, Ph.D.; Rob Gealy; Alea Melacrino; Herng der Chern, M.D.; and Raj Persad, M.D.
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