Catecholestrogens as mediators of carcinogenesis: correlation of aromatic hydroxylation of estradiol and its fluorinated analogs with tumor induction in Syrian hamsters.
17 beta-Estradiol is known to induce kidney tumors in male Syrian hamsters when administered chronically, whereas 4-fluoroestradiol does so only after an extended induction period and 2-fluoroestradiol is not carcinogenic; both fluorinated analogs are hormonally active. Because C-4 and C-2 hydroxylations are, respectively, minor and major routes of estrogen metabolism in vivo, these observations suggest mediation of tumorigenesis by catecholestrogen metabolites. However, the analogs were reported to undergo oxidative defluorination in vitro. We have determined the metabolic fates of estradiol, 2-fluoroestradiol, and 4-fluoroestradiol in male hamsters. [6,7-3H]Estradiol was principally C-2 hydroxylated when given intravenously at either 0.1 mumol/kg or 50 mumol/kg; 2-hydroxyestradiol was eliminated in bile and urine, largely as a glucuronide, without undergoing extensive deactivation via O-methylation. Alicyclic alcohol metabolites were minor products. [6,7-3H]2-Fluoroestradiol underwent either glucuronylation or sequential dehydrogenation and alicyclic hydroxylation followed by glucuronylation but neither oxidative defluorination nor compensatory C-4 hydroxylation. [6,7-3H]4-Fluoroestradiol was also considerably dehydrogenated to the keto form and glucuronylated. Nevertheless, only 4-fluoroestradiol yielded appreciable quantities of C-2 hydroxylated metabolite at the lower dose; methylation was an insignificant pathway. No defluorinated products were observed. Dehydrogenation of both analogs and alicyclic hydroxylation of the 2-fluoroestrone metabolite were less extensive at the higher dose; all of the polar metabolites of 2-fluoroestradiol in bile, although not those in urine, declined to trace amounts. C-2 hydroxylation of 4-fluoroestradiol was greater at this dose. Thus, the rank order of catechol formation from estradiol and its fluoro analogs observed in vivo, unlike that found in microsomal incubations, was consistent with the hypothesis that catechols mediate estrogen-dependent renal carcinogenesis in hamsters.
Stalford
A C
AC
Department of Pharmacology and Therapeutics, University of Liverpool, England.
Maggs
J L
JL
Gilchrist
T L
TL
Park
B K
BK
D000818:Animals; D001646:Bile / Q000378:metabolism; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D006224:Cricetinae; D004958:Estradiol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D002393:Estrogens, Catechol / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D006900:Hydroxylation; D007680:Kidney Neoplasms / Q000139:chemically induced*; D008297:Male; D008647:Mesocricetus; D014316:Tritium
D002273:Carcinogens; D002393:Estrogens, Catechol; D014316:Tritium; C037475:2-fluoroestradiol; C037810:4-fluoroestradiol; D004958:Estradiol