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 hams ters when administered chronically, whereas 4-fluoroestradiol does so only after an extended induction period and 2-fluoroestradiol is not c arcinogenic; 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 we re reported to undergo oxidative defluorination in vitro. We have dete rmined the metabolic fates of estradiol, 2-fluoroestradiol, and 4-fluo roestradiol in male hamsters. [6,7-H-3]Estradiol was principally C-2 h ydroxylated when given intravenously at either 0.1 mu mol/kg or 50 mu mol/kg; 2-hydroxyestradiol was eliminated in bile and urine, largely a s a glucuronide, without undergoing extensive deactivation via O-methy lation. Alicyclic alcohol metabolites were minor products. [6,7-H-3]2- Fluoroestradiol underwent either glucuronylation or sequential dehydro genation and alicyclic hydroxylation followed by glucuronylation but n either oxidative defluorination nor compensatory C-4 hydroxylation. [6 ,7-H-3]4-Fluoroestradiol was also considerably dehydrogenated to the k eto form and glucuronylated. Nevertheless, only 4-fluoroestradiol yiel ded appreciable quantities of C-2 hydroxylated metabolite at the lower dose; methylation was an insignificant pathway. No defluorinated prod ucts were observed. Dehydrogenation of both analogs and alicyclic hydr oxylation of the 2-fluoroestrone metabolite were less extensive at the higher dose; all of the polar metabolites of 2-fluoroestradiol in bil e, although not those in urine, declined to trace amounts. C-2 hydroxy lation of 4-fluoroestradiol was greater at this dose. Thus, the rank o rder of catechol formation from estradiol and its fluoro analogs obser ved in vivo, unlike that found in microsomal incubations, was consiste nt with the hypothesis that catechols mediate estrogen-dependent renal carcinogenesis in hamsters.