Search

Your search keyword '"Krueger, Sharon K."' showing total 40 results
Start Over Author "Krueger, Sharon K."
40 results on '"Krueger, Sharon K."'

16. Dibenzo[def,p]chrysene transplacental carcinogenesis in wild-type,Cyp1b1knockout, andCYP1B1humanized mice

Author

Madeen, Erin P., primary, Löhr, Christiane V., additional, You, Hannah, additional, Siddens, Lisbeth K., additional, Krueger, Sharon K., additional, Dashwood, Roderick H., additional, Gonzalez, Frank J., additional, Baird, William M., additional, Ho, Emily, additional, Bramer, Lisa, additional, Waters, Katrina M., additional, and Williams, David E., additional

Published
2016
Full Text
View/download PDF

25. In utero Exposure of Mice to Dibenzo[a,l]Pyrene Produces Lymphoma in the Offspring: Role of the Aryl Hydrocarbon Receptor

Author

Yu, Zhen, primary, Loehr, Christiane V., additional, Fischer, Kay A., additional, Louderback, Mandy A., additional, Krueger, Sharon K., additional, Dashwood, Roderick H., additional, Kerkvliet, Nancy I., additional, Pereira, Clifford B., additional, Jennings-Gee, Jamie E., additional, Dance, Stephanie T., additional, Miller, Mark Steven, additional, Bailey, George S., additional, and Williams, David E., additional

Published
2006
Full Text
View/download PDF

37. Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse.

Author

Palmer, Amy L., Leykam, Virginia L., Larkin, Andrew, Krueger, Sharon K., Phillips, Ian R., Shephard, Elizabeth A., and Williams, David E.

Subjects
DRUG resistance in microorganisms, PHARMACOKINETICS, MONOOXYGENASES, LABORATORY mice, MYCOBACTERIAL diseases, DRUG metabolism
Abstract

Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA. [ABSTRACT FROM AUTHOR]

Published
2012
Full Text
View/download PDF

38. Identification and functional analysis of common human flavin-containing monooxygenase 3 genetic variants.

Author

Koukouritaki, Sevasti B, Poch, Mark T, Henderson, Marilyn C, Siddens, Lisbeth K, Krueger, Sharon K, Vandyke, Jonathan E, Williams, David E, Pajewski, Nicholas M, Wang, Tao, and Hines, Ronald N

Abstract

Flavin-containing monooxygenases (FMOs) are important for the disposition of many therapeutics, environmental toxicants, and nutrients. FMO3, the major adult hepatic FMO enzyme, exhibits significant interindividual variation. Eighteen FMO3 single-nucleotide polymorphism (SNP) frequencies were determined in 202 Hispanics (Mexican descent), 201 African Americans, and 200 non-Latino whites. Using expressed recombinant enzyme with methimazole, trimethylamine, sulindac, and ethylenethiourea, the novel structural variants FMO3 E24D and K416N were shown to cause modest changes in catalytic efficiency, whereas a third novel variant, FMO3 N61K, was essentially devoid of activity. The latter variant was present at an allelic frequency of 5.2% in non-Latino whites and 3.5% in African Americans, but it was absent in Hispanics. Inferring haplotypes using PHASE, version 2.1, the greatest haplotype diversity was observed in African Americans followed by non-Latino whites and Hispanics. Haplotype 2A and 2B, consisting of a hypermorphic promoter SNP cluster (-2650C>G, -2543T>A, and -2177G>C) in linkage with synonymous structural variants was inferred at a frequency of 27% in the Hispanic population, but only 5% in non-Latino whites and African Americans. This same promoter SNP cluster in linkage with one or more hypomorphic structural variant also was inferred in multiple haplotypes at a total frequency of 5.6% in the African-American study group but less than 1% in the other two groups. The sum frequencies of the hypomorphic haplotypes H3 [15,167G>A (E158K)], H5B [-2650C>G, 15,167G>A (E158K), 21,375C>T (N285N), 21,443A>G (E308G)], and H6 [15,167G>A (E158K), 21,375C>T (N285N)] was 28% in Hispanics, 23% in non-Latino whites, and 24% in African Americans.

Published
2007
Full Text
View/download PDF

39. Assessment of methyl p-tolyl sulfoxidation by human FMO2.1, p.S195L and p.N413K flavin-containing monooxygenase variant.

Author

Krueger, Sharon K., Henderson, Marilyn C., Siddens, Lisbeth K., VanDyke, Jonathan E., Fumes, Bjarte, Schlenk, Daniel, and Williams, David E.

Subjects
*MONOOXYGENASES, *FLAVINS, *MEMBRANE proteins, *PHYSIOLOGICAL oxidation, *PHYSIOLOGICAL effects of magnesium, *GENETIC mutation
Abstract

Previous work identified two common ethnically-dependent allelic variants of human flavin-containing monooxygenase 2 (FMO2) that encode protein with monooxygenase activity that could occur in combination with the functional FM02*1 allele (Q472 protein); the encoded proteins were S195L and N413K. To understand how these variants alter enzyme activity, we performed assays with the FMO substrate, methyl p-tolyl sulfide (MTS) under a range of conditions with S195L, N413K and Q472 produced by over-expression in Sf9 insect cells. MTS sulfoxidation was assayed by HPLC. All protein variants demonstrated the same pattern of response to the presence of magnesium (increased activity) and to heat (decreased activity). Increased activity was observed with Q472 and N413K in response to increasing pH and to cholate, while S195L had diminished activity. The major effect of the N413K substitution was to increase velocity compared with Q472, while S195L had reduced activity and altered patterns of response to incubation conditions. In contrast to Q472 and N413K, S195L activity was negligible unless NADPH was added before MTS. Also, the K,, for S195L is at least 10-fold higher than for Q472 and N413K. Although these allelic variants are expected to occur infrequently as mutations to the FM02*1 allele, they contribute to our overall understanding of mammalian FMO structure and function. [ABSTRACT FROM AUTHOR]

Published
2007

40. Alpha-tocopherol modulates Cyp3a expression, increases gamma-CEHC production, and limits tissue gamma-tocopherol accumulation in mice fed high gamma-tocopherol diets.

Author

Traber MG, Siddens LK, Leonard SW, Schock B, Gohil K, Krueger SK, Cross CE, and Williams DE

Subjects
Animals, Antioxidants pharmacology, Blotting, Western, Brain pathology, Carrier Proteins genetics, Carrier Proteins physiology, Cytochrome P-450 CYP3A, Genotype, Humans, Liver metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oxygen metabolism, Time Factors, Vitamin E metabolism, Xenobiotics, alpha-Tocopherol metabolism, gamma-Tocopherol metabolism, Animal Feed, Aryl Hydrocarbon Hydroxylases biosynthesis, Chromans metabolism, Oxidoreductases, N-Demethylating biosynthesis, Propionates metabolism, alpha-Tocopherol pharmacology, gamma-Tocopherol pharmacology
Abstract

Although all forms of vitamin E are absorbed, the liver preferentially secretes alpha-, but not gamma-tocopherol, into plasma. Liver alpha-tocopherol secretion is under the control of the alpha-tocopherol transfer protein (TTP). Therefore, to assess gamma-tocopherol bioactivities Ttpa-/-, +/- and +/+ mice were fed for 5 weeks diets containing gamma-tocopherol 550 (gamma-T550), gamma-tocopherol 60 (gamma-T60) mg/kg that also contained trace amounts of alpha-tocopherol, a vitamin E-deficient diet, or a control diet. Plasma and tissues from mice fed gamma-T550 diets were found to contain similar gamma- and alpha-tocopherol concentrations despite the high dietary gamma-tocopherol content; nervous tissues contained almost no gamma-tocopherol. Liver vitamin E metabolites (carboxyethyl hydroxychromans, CEHCs) were also measured. In mice with widely ranging liver alpha- (from 0.7 to 16 nmol/g) and gamma-tocopherol concentrations (0 to 13 nmol/g), hepatic alpha-CEHC was undetectable, but gamma-CEHC concentrations (0.1 to 0.8 nmol/g) were correlated with both alpha- and gamma-tocopherol concentrations (P < 0.004). Hepatic cytochrome P450s (CYPs) involved in vitamin E metabolism, Cyp4f and Cyp3a, were also measured. There were no variations in Cyp4f protein expression as related to diet or mouse genotype. However, Cyp3a was correlated (P < 0.0001) with liver alpha-, but not gamma-tocopherol concentrations. These data support the hypothesis that alpha-tocopherol modulates xenobiotic metabolism by increasing Cyp3a expression, gamma-CEHC formation, and the excretion of both gamma-tocopherol and gamma-CEHC.

Published
2005
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results