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

Carcinogenesis. 2002 Feb;23(2):329-33. doi: 10.1093/carcin/23.2.329.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Caprylates / pharmacology
  • Catechol O-Methyltransferase / pharmacology
  • Chromatography, High Pressure Liquid
  • Dimethyl Sulfoxide / pharmacology
  • Estradiol / analogs & derivatives*
  • Estradiol / pharmacology*
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Estrogens, Catechol / metabolism*
  • Estrogens, Catechol / 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

Substances

  • 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