Extrahepatic cytochrome P450s - Relation to cancer susceptibility

摘要: Cytochrome P450 (CYP) enzymes in extrahepatic tissues may play important roles regulating the capacity of individual cells to metabolize environmental carcinogens and hormones. In this thesis, we characterized cytochrome profile human normal breast investigated whether polymorphisms genes encoding estrogen metabolizing CYP1B1 Catechol-O-methyltransferase (COMT) were associated with or endometrial cancer risk. We also identified, cloned novel 2S1 (CYP2S1) enzyme a possible role metabolism xenobiotics. Detected levels CYP are generally lower than liver thus difficult measure. By partial purification CYPs from reduction samples, spectrally quantified level be approximately 1000-fold liver. expression pattern by RT-PCR Western blot 15 samples found involved carcinogens, steroid hormones drugs. A large interindividual variation CYP1A1, 2A6, 2B6, 2D6 3A shown whereas CYP1B1, 2C, 2E1, 4A 19 present most samples. Molecular epidemiological studies on association between polymorphic variants biosynthesis hormonal risk published rapidly increasing frequency. However, reported data inconsistent, partly due small sample sizes. COMT genotypes, respectively, (only CYP1B1) population-based case-control study Swedish postmenopausal women. genotyped 1 500 cases, 690 cases controls calculated odds ratios 95 percent confidence intervals conditional logistic regression models. no overall genotype Stratified analyses indicated that CYP1B1*3/*3 importance conjunction menopausal hormone use low activity allele appeared an increased for lobular cancer. had effect risk, neither nor subgroup analyses. The CYP2S1 gene was identified through homology searches known sequences against EST database high throughput genomic database. located together subfamily CYP2A, CYP2B CYP2F chromosome 19. predicted 504 amino acid sequence displayed 38-49 identity other CYP2 family members contained typical structural characteristics; conserved cystein, proline rich region N-terminal hydrophobic stretch. mRNA highly expressed lung, trachea, stomach. transcript detected but at levels. rabbit peptide antiserum C-terminus recognized single band lung apparent molecular weight 50 kD. Subcellular localization immunocytochemistry revealed microsomal protein. High respiratory gastrointestinal tract indicates xenobiotic metabolism. Unpublished observations our lab show aromatic hydrocarbons appear substrates CYP2S1. summary, work have contributed understanding presence tissues, particularly evaluated genetic relation susceptibility. LIST OF PUBLICATIONS I. Hellmold H, Rylander T, Magnusson M, Reihner E, Warner M Gustafsson J-A (1998) Characterization tissue mammaplasties Journal Clinical Endocrinology Metabolism, 83:886-895 II Rylander-Rudqvist Wedren S, Granath F, Humphreys K, Ahlberg Weiderpass Oscarson Ingelman-Sundberg Ingemar Persson (2003) 1B1 Carcinogenesis, 24:1533-1539 III. Jonasdottir G, I Manuscript IV. C polymorphism 24:681-687 V. Neve (2001) Identification distribution Biochemical Biophysical Research Communications, 281:529-535