Constitutive expression of bioactivating enzymes in normal human prostate suggests a capability to activate pro-carcinogens to DNA-damaging metabolites.
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.
Martin
Francis L
FL
Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Lancaster, UK. f.martin@lancaster.ac.uk
Patel
Imran I
II
Sozeri
Osman
O
Singh
Paras B
PB
Ragavan
Narasimhan
N
Nicholson
Caroline M
CM
Frei
Eva
E
Meinl
Walter
W
Glatt
Hansruedi
H
Phillips
David H
DH
Arlt
Volker M
VM
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
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