Title: Catechol estrogen metabolites and conjugates in different regions of the prostate of Noble rats treated with 4-hydroxyestradiol: implications for estrogen-induced initiation of prostate cancer.
Authors: Cavalieri, Ercole L; Devanesan, Prabu; Bosland, Maarten C; Badawi, Alaa F; Rogan, Eleanor G
Published In Carcinogenesis, (2002 Feb)
Abstract: Prostate carcinomas arise in 100% of Noble rats treated with estradiol and testosterone. We hypothesize that estrogens initiate prostate cancer mainly by formation of 4-catechol estrogens (CE), followed by their oxidation to catechol estrogen-3,4-quinones (CE-3,4-Q), which can react with DNA. To avoid cancer initiation, CE can be detoxified by catechol-O-methyltransferase (COMT), and CE-3,4-Q by conjugation with glutathione (GSH) or by reduction to CE, catalyzed by quinone reductase and/or cytochrome P450 reductase. To investigate the prostatic metabolism of estrogens, Noble rats were treated with the CE 4-hydroxyestradiol (4-OHE2) or estradiol-3,4-quinone (E2-3,4-Q), and CE metabolites and conjugates were analyzed in the four regions of the prostate, which differ in susceptibility to carcinoma formation. Following treatment of rats with 4-OHE2 (6 micromol/100 g body weight in 200 microl of trioctanoin/dimethylsulfoxide (4:1) by intraperitoneal injection) for 90 min, the non-susceptible ventral (VP) and anterior (AP) prostate had higher levels of 4-methoxyCE and GSH conjugates than the susceptible dorsolateral prostate (DLP) and periurethral prostate (PUP). After treatment with the same molar amount of E2-3,4-Q, the VP and AP contained more GSH conjugates, 4-CE and 4-methoxyCE than the susceptible DLP and PUP. These results suggest that prostate areas susceptible to carcinoma induction have less protection by COMT, GSH, and quinone reductase and/or cytochrome P450 reductase, favoring reaction of CE-3,4-Q with DNA, presumably to initiate cancer.
PubMed ID: 11872641
MeSH Terms: Animals; Caprylates/pharmacology; Catechol O-Methyltransferase/pharmacology; Chromatography, High Pressure Liquid; Dimethyl Sulfoxide/pharmacology; Estradiol/analogs & derivatives*; Estradiol/pharmacology*; Estrogens, Catechol/metabolism*; Estrogens, Catechol/pharmacology; Estrogens/metabolism; Estrogens/pharmacology; Excipients/pharmacology; Glutathione/metabolism; Male; Models, Chemical; NAD(P)H Dehydrogenase (Quinone)/metabolism; NADPH-Ferrihemoprotein Reductase/metabolism; Prostate/drug effects*; Prostatic Neoplasms/chemically induced*; Prostatic Neoplasms/etiology; Prostatic Neoplasms/metabolism*; Protein Binding; Rats; Testosterone/pharmacology; Time Factors; Triglycerides/pharmacology; Urethra/metabolism