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.

CONCLUSION:

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: Francis L Martin, Imran I Patel, Osman Sozeri, Paras B Singh, Narasimhan Ragavan, Caroline M Nicholson, Eva Frei, Walter Meinl, Hansruedi Glatt, David H Phillips, Volker M Arlt
• Journal: The Prostate (Prostate) Vol. 70 Issue 14 Pg. 1586-99 (Oct 01 2010) ISSN: 1097-0045 [Electronic] United States
• PMID: 20687231 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 Wiley-Liss, Inc.

Chemical References

• Carcinogens
• DNA Adducts
• Sex Hormone-Binding Globulin
• Testosterone
• Estradiol
• Aryl Hydrocarbon Hydroxylases
• CYP1B1 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP1A2
• Cytochrome P-450 CYP1B1
• Amino-Acid N-Acetyltransferase

Topics

• Aged
• Aged, 80 and over
• Amino-Acid N-Acetyltransferase (genetics)
• Aryl Hydrocarbon Hydroxylases (genetics)
• Blotting, Western
• Carcinogens (metabolism)
• Cytochrome P-450 CYP1A1 (genetics)
• Cytochrome P-450 CYP1A2 (genetics)
• Cytochrome P-450 CYP1B1
• DNA Adducts (metabolism)
• DNA Damage
• Estradiol (blood)
• Gene Expression Regulation
• Humans
• Male
• Middle Aged
• Prostate (enzymology, pathology, physiology)
• Prostatectomy
• Sex Hormone-Binding Globulin (metabolism)
• Testosterone (blood)