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.
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.
Cavalieri
Ercole L
EL
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805, USA. ecavaalie@unmc.edu
Devanesan
Prabu
P
Bosland
Maarten C
MC
Badawi
Alaa F
AF
Rogan
Eleanor G
EG
D000818:Animals; D002210:Caprylates / Q000494:pharmacology; D002394:Catechol O-Methyltransferase / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D002393:Estrogens, Catechol / Q000378:metabolism* / Q000494:pharmacology; D005079:Excipients / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011467:Prostate / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000209:etiology / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D013739:Testosterone / Q000494:pharmacology; D013997:Time Factors; D014280:Triglycerides / Q000494:pharmacology; D014521:Urethra / Q000378:metabolism
D002210:Caprylates; D004967:Estrogens; D002393:Estrogens, Catechol; D005079:Excipients; D014280:Triglycerides; C116356:catechol estrogen 3,4-quinone; D013739:Testosterone; D004958:Estradiol; C003637:tricaprylin; C014036:4-hydroxyestradiol; D009251:NADPH-Ferrihemoprotein Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); D002394:Catechol O-Methyltransferase; D005978:Glutathione; D004121:Dimethyl Sulfoxide