Polymorhphisms in the Gene for Microsomal Epoxide Hydrolase--Possible Answer to "Why Me?"

William Gauderman and Kimberly Siegmund
University of Southern California
R01ES10421

Background: One of the most puzzling questions in medicine and science is why people with similar environments and life-styles have differences in cancer incidence. For instance, why do some smokers develop lung cancer and others remain cancer free? One probable reason is differences in genetic makeup. These gene/environment interactions are a major focus of research supported and conducted by NIEHS.

Colon cancer has been linked in several research studies to exposure to polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke and meats cooked well-done. The potential for these compounds to cause cancer may be dependent on the length and amount of exposure and their activation or inactivation by metabolic enzymes. Differences or polymorphisms in the genes coding for these enzymes have been found. A person may be more or less susceptible to the carcinogenic effects of PAHs depending on which polymorphisms they have in their genetic make-up for a variety of enzymes.

Advance: This report focuses on polymorphisms for microsomal epoxide hydrolase (mEH), an enzyme involved in PAH metabolism. Among individuals who have high mEH enzyme activity, smoking and consumption of well-done red meat were significantly associated with the presence of colon adenoma. Differences in inactivation and excretion of PAHs due to mutations in glutatione S-transferase M3 may also be involved.

Implication: These results suggest that mEH activity is associated with a risk for colorectal adenomas when environmental exposures and other response mediating genes are taken into account. They also suggests that at least part of the increased risk for adenoma is associated with smoking and the consumption of well-done red meat. Both lifestyle factors are consistent with PAH exposure. This paper illustrates how gene regulation of enzyme activity may at least partially explain differences in disease state and exposure response in people living in similar environments.

Publication: Cortessis V, Siegmund K, Chen Q, Zhou N, Diep A, Frankl H, Lee E, Zhu QS, Haile R, Levy D. A case-control study of microsomal epoxide hydrolase, smoking, meat consumption, glutathione S-transferase M3, and risk of colorectal adenomas. Cancer Res. 2001 Mar 15;61(6):2381-5.