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The Cancer Chemoprotection Program

Role of Drug-metabolizing Enzymes in Health and Disease

Principal Investigator: Sharon Krueger, Ph.D.

The flavin-containing monooxygenases (FMOs) and cytochrome P450s (CYPs) are enzymes that oxygenate many of the drugs and chemicals that we ingest, inhale, or absorb. I am interested in the role these enzymes play in modulating disease and the impact of genetic variants on metabolism, especially in cancer and tuberculosis. Sulindac is an anti-inflammatory drug used to treat individuals with familial adenomatous polyposis (FAP), an inherited disorder characterized by colorectal cancer. FMO3 oxygenates sulindac sulfide, leading to its increased excretion. Studies have shown that among individuals with FAP, those with FMO3 polymorphisms (genetic variations) that have a reduced capacity to oxygenate and excrete sulindac have a reduced polyp and tumor burden. A human study has demonstrated that dietary consumption of Brussels sprouts decreases conversion of trimethylamine to trimethylamine N-oxide, another reaction catalyzed by FMO3. We are investigating the hypothesis that consumption of Brussels sprouts will reduce and delay sulindac oxygenation. If this is correct, dietary regulation of FMO3 could become a strategy for enhancing and prolonging the efficacy of sulindac and reducing the impact of FAP.

Whereas FMO3 is the predominant FMO in human liver, FMO2 is the dominant isoform in lung. However, only some individuals of African or Hispanic/Latino descent produce active protein; all other populations have a polymorphism for FMO2, rendering them with little capacity for metabolism of FMO substrates in the lung. Several classes of anti-tuberculosis drugs require activation by FMOs for bactericidal activity. Mycobacteria (causative agents for TB and leprosy) have their own FMO that activates these drugs. We have hypothesized that people with active FMO2 who have TB and are treated with these drugs will have a different drug response (toxicity and efficacy) from people without active FMO2. We are testing this hypothesis using mice with and without FMO2, and if correct, physicians may have a strategy to tailor drug therapy for TB on the basis of FMO2 polymorphism.