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.

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.

• Authors: Ercole L Cavalieri, Prabu Devanesan, Maarten C Bosland, Alaa F Badawi, Eleanor G Rogan
• Journal: Carcinogenesis (Carcinogenesis) Vol. 23 Issue 2 Pg. 329-33 (Feb 2002) ISSN: 0143-3334 [Print] England
• PMID: 11872641 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Caprylates
• Estrogens
• Estrogens, Catechol
• Excipients
• Triglycerides
• catechol estrogen 3,4-quinone
• Testosterone
• Estradiol
• tricaprylin
• 4-hydroxyestradiol
• NADPH-Ferrihemoprotein Reductase
• NAD(P)H Dehydrogenase (Quinone)
• Catechol O-Methyltransferase
• Glutathione
• Dimethyl Sulfoxide

Topics

• Animals
• Caprylates (pharmacology)
• Catechol O-Methyltransferase (pharmacology)
• Chromatography, High Pressure Liquid
• Dimethyl Sulfoxide (pharmacology)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogens (metabolism, pharmacology)
• Estrogens, Catechol (metabolism, 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, etiology, metabolism)
• Protein Binding
• Rats
• Testosterone (pharmacology)
• Time Factors
• Triglycerides (pharmacology)
• Urethra (metabolism)