Research Assistant Professor, Linus Pauling Institute
Office: 459 Linus Pauling Science Center
Telephone: (541) 737-9322
Fax: (541) 737-5077
Email Address: email@example.com
Mailing/Express Delivery Address:
Sharon K. Krueger, Ph.D.
Linus Pauling Institute
Oregon State University
307 Linus Pauling Science Center
Corvallis, OR 97331
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.
||B.S., Horticulture, University of Wisconsin-Madison
||M.S., Plant Breeding and Plant Genetics, University of Wisconsin-Madison
||Ph.D., Plant Breeding, Oregon State University
||Faculty Research Assistant, Department of Botany and Plant Pathology, Oregon State University
||Research Associate, Department of Fisheries and Wildlife, Oregon State University
||Instructor, Department of Zoology, Oregon State University
||Research Associate, Department of Environmental and Molecular Toxicology, Oregon State University
||Research Assistant Professor, Linus Pauling Institute, Oregon State University
American Association for the Advancement of Science
International Society for the Study of Xenobiotics
Pacific Northwest Association of Toxicologists
Society of Toxicology
Tilton SC, Siddens LK, Krueger SK, Larkin AJ, Löhr CV, Williams DE, Baird WM, Waters KM. (2015) Mechanism-based classification of PAH mixtures to perduct carcinogenic potential. Toxicol Sci, Epub ahead of print.
Henderson MC, Siddens LK, Krueger SK, Stevens JF, Kedzie K, Fang WK, Heidelbaugh T, Nguyen P, Chow K, Garst M, Gil D, Williams DE. (2014) Flavin-containing monoxygenase S-oxygenation of a series of thioureas and thiones. Toxicol Appl Pharmacol 278:91-99.
Siddens LK, Krueger SK, Henderson MC, Williams DE. (2014) Mammalian flavin-containing monooxygenase (FMO) as a source of hydrogen peroxide. Biochem Pharmacol 89:141-147.
Larkin A, Siddens LK, Krueger SK, Tilton SC, Waters KM, Williams DE, Baird WM. (2013) Application of a fuzzy neural network model in predicting polycyclic aromatic hydrocarbon-mediated perturbations of the Cyp1b1 transcriptional regulatory network in mouse skin. Toxicol Appl Pharmacol 267:192-199.
Palmer AL, Leykam VL, Larkin A, Krueger SK, Phillips IR, Shephard EA, Williams DE. (2012) Metabolism and pharmacokinetics of the anti-tuberculosis drug ethionamide in a flavin-containing monooxygenase null mouse. Pharmaceuticals(Basel) 5:1147-1159.
Siddens LK, Larkin A, Krueger SK, Bradfield CA, Waters KM, Tilton SC, Pereira CB, Löhr CV, Arlt VM, Phillips DH, Williams DE, Baird WM. (2012) Polycyclic aromatic hydrocarbons as skin carcinogens: comparison of benzo[a]pyrene, dibenzo[def,p]chrysene and three environmental mixtures in the FVB/N mouse. Toxicol Appl Pharmacol 264:377-386.
Celius T, Pansoy A, Matthews J, Okey AB, Henderson MC, Krueger SK, Williams DE (2010) Flavin-containing monooxygenase-3: induction by 3-methylcholanthrene and complex regulation by xenobiotic chemicals in hepatoma cells and mouse liver. Toxicol Appl Pharmacol 247:60-69.
Krueger SK, Henderson MC, Siddens LK, VanDyke JE, Benninghoff AD, Karplus PA, Furnes B, Schlenk D, Williams DE (2009) Characterization of sulfoxygenation and structural implications of human flavin-containing monooxygenase isoform 2 (FMO2.1) variants S195L and N413K. Drug Metab Dispos 37:1785-1791.