title: Unbalanced estrogen metabolism in ovarian cancer.
abstract: Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer.
authors.affiliation: Department of Environmental Agricultural and Occupational Health College of Public Health, University of Nebraska Medical Center, Omaha, NE.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zahid
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Beseler
authors.forename: James B
authors.initials: JB
authors.lastname: Hall
authors.forename: Tricia
authors.initials: T
authors.lastname: LeVan
authors.forename: Ercole L
authors.initials: EL
authors.lastname: Cavalieri
authors.forename: Eleanor G
authors.initials: EG
authors.lastname: Rogan
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D004273:DNA, Neoplasm / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism / Q000652:urine*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000652:urine; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012463:Saliva / Q000737:chemistry / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D018736:DNA Adducts; D004273:DNA, Neoplasm; D004967:Estrogens; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1; D002394:Catechol O-Methyltransferase
keywords: CYP1B1; SNPs; catechol-O-methyltransferase; ovarian cancer, estrogen-DNA adducts, unbalanced estrogen metabolism