title: Constitutive expression of bioactivating enzymes in normal human prostate suggests a capability to activate pro-carcinogens to DNA-damaging metabolites.
abstract: BACKGROUND
  The constitutive bioactivating capacity of human prostate may play a role in determining risk of adenocarcinoma developing in this tissue. Expression of candidate enzymes that convert exogenous and/or endogenous agents into reactive DNA-damaging species would suggest the potential to generate initiating events in prostate cancer (CaP).
  
  
  METHODS
  Normal prostate tissues from UK-resident Caucasians (n = 10) were collected following either radical retropubic prostatectomy (RRP) or cystaprostatectomy (CyP). An analysis of gene and protein expression of candidate metabolizing enzymes, including cytochrome P450 (CYP)1A1, CYP1A2, CYP1B1, N-acetyltransferase 1 (NAT1), sulfotransferase (SULT)1A1, SULT1A3, NAD(P)H:quinone oxidoreductase (NQO1), prostaglandin H synthase 1 (cyclooxygenase 1; COX1), and CYP oxidoreductase (POR) was carried out. Quantitative real-time reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemical analysis were conducted.
  
  
  RESULTS
  Except for CYP1A1 and CYP1A2, the metabolizing enzymes examined appeared to be expressed with minimal inter-individual variation (in general, approximately two- to fivefold) in the expression levels. Enzymes such as CYP1B1 and NQO1 that are capable of bioactivating pro-carcinogens to reactive metabolites were readily identifiable in human prostate. Immunohistochemical analysis showed that although some expression is located in the stroma, the majority is localized to epithelial cells lining the glandular elements of the tissue; these are the cells from which CaP might arise.
  
  
  CONCLUSIONS
  Constitutive expression of bioactivating enzymes confers the potential to convert a range of exogenous and/or endogenous agents to reactive species capable of inducing DNA damaging events. These findings suggest an organ capability for pro-carcinogen activation that could play an important role in the etiology of human CaP.
authors.affiliation: Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Lancaster, UK. f.martin@lancaster.ac.uk
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
authors.forename: Imran I
authors.initials: II
authors.lastname: Patel
authors.forename: Osman
authors.initials: O
authors.lastname: Sozeri
authors.forename: Paras B
authors.initials: PB
authors.lastname: Singh
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Ragavan
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Nicholson
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.forename: Walter
authors.initials: W
authors.lastname: Meinl
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051046:Amino-Acid N-Acetyltransferase / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015153:Blotting, Western; D002273:Carcinogens / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D004958:Estradiol / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011467:Prostate / Q000201:enzymology / Q000473:pathology / Q000502:physiology*; D011468:Prostatectomy; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D004958:Estradiol; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D051046:Amino-Acid N-Acetyltransferase