title: Metabolic activation of carcinogens and expression of various cytochromes P450 in human prostate tissue.
abstract: Epidemiological evidence suggests a link between meat consumption and prostate cancer. In this study, benign prostatic hyperplasia tissues, obtained by transurethral resection or radical retropubic prostatectomy from UK-resident individuals (n = 18), were examined for CYP1 expression and for their ability, in short-term organ culture, to metabolically activate carcinogens found in cooked meat. Semi-quantitative RT-PCR analysis of CYP1 expression detected CYP1A2 mRNA transcripts in the prostates of four individuals, as well as mRNA transcripts from CYP1A1 and CYP1B1. The compounds tested for metabolic activation were 2-amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP; 500 microM, n = 9) and its metabolite N:-hydroxy PhIP (20 microM, n = 8), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ; 500 microM, n = 6) and benzo[a]pyrene (B[a]P; 50 microM, n = 5). After incubation (PFMR medium, 22 h, 37 degrees C), DNA was isolated from tissue fragments and DNA adducts were detected and quantified by (32)P-postlabelling analysis. DNA adduct formation was detected in all samples incubated with PhIP (mean, adducts per 10(8) nucleotides), N:-hydroxy-PhIP (2736/10(8)) or B[a]P (1/10(8)). IQ-DNA adducts were detected in 5/6 tissues (mean, 1/10(8)). The CYP1 inhibitor alpha-naphthoflavone (10 microM) reduced B[a]P-DNA adduct formation in tissues from two individuals by 96 and 64%, respectively. This pilot study shows that human prostate tissue can metabolically activate 'cooked meat' carcinogens, a process that could contribute to prostate cancer development.
authors.affiliation: Institute of Cancer Research, Haddow Laboratories, Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Williams
authors.forename: F L
authors.initials: FL
authors.lastname: Martin
authors.forename: G H
authors.initials: GH
authors.lastname: Muir
authors.forename: A
authors.initials: A
authors.lastname: Hewer
authors.forename: P L
authors.initials: PL
authors.lastname: Grover
authors.forename: D H
authors.initials: DH
authors.lastname: Phillips
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D008297:Male; D009924:Organ Culture Techniques; D011468:Prostatectomy; D011470:Prostatic Hyperplasia / Q000201:enzymology* / Q000235:genetics / Q000601:surgery; D011725:Pyridines / Q000493:pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D007093:Imidazoles; D011725:Pyridines; D011804:Quinolines; D012333:RNA, Messenger; C060533:2-hydroxyamino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D001564:Benzo(a)pyrene; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1