Correlation of aromatic hydroxylation of 11β-substituted estrogens with morphological transformation in vitro but not with in vivo tumor induction by these hormones

In estrogen-induced cancer, catechol formation from administered steroids has been postulated to be a necessary event for estrogen activation and subsequent damage to cellular macromolecules. In the present study, this hypothesis has been tested using two homologous series of structurally related es...

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Published in:	Cancer research (Chicago, Ill.) Vol. 47; no. 10; pp. 2583 - 2588
Main Authors:	LIEHR, J. G, PURDY, R. H, BARAN, J. S, NUTTING, E. F, COLTON, F, RANDERATH, R, RANDERATH, K
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-05-1987
Subjects:	Animals Biological and medical sciences Carcinogenesis, carcinogens and anticarcinogens Cell Transformation, Neoplastic - metabolism Chemical agents Cricetinae DNA - metabolism Estrogens - metabolism Estrogens, Catechol - metabolism Female Hydroxylation Kidney - metabolism Kidney - ultrastructure Male Medical sciences Mesocricetus Mice Mice, Inbred BALB C Microsomes - metabolism Neoplasms, Hormone-Dependent - metabolism Rats Rats, Inbred Strains Tumors Cell culture Animal model Hydroxylation Steroid hormone Rodentia Estrogen Metabolism toxicity relation Tumorigenicity Cell transformation In vitro Kidney In vivo Vertebrata Mammalia Catechol estrogen Experimental tumor Comparative study Hamster
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Summary:	In estrogen-induced cancer, catechol formation from administered steroids has been postulated to be a necessary event for estrogen activation and subsequent damage to cellular macromolecules. In the present study, this hypothesis has been tested using two homologous series of structurally related estrogens: estradiol, 11 beta-methylestradiol, 11 beta-ethylestradiol, 11 beta-methyl-17 alpha-ethinylestradiol, 11 beta-ethyl-17 alpha-ethinylestradiol, 11 beta-methoxy-17 alpha-ethinylestradiol, and 17 alpha-ethinylestradiol. In the Syrian hamster renal carcinoma model, only 11 beta-methylestradiol and 17 alpha-ethinylestradiol were weak carcinogens (2 of 20 and 2 of 24 hamsters with tumors, respectively). The other estrogens tested induced renal carcinoma within 6 to 9 months with an incidence in the 80-100% range. The tumor incidence in vivo did not correlate with the rates of catechol formation by hamster kidney microsomes in vitro. Compared to estradiol (relative rate, 100), catechol formation by the substituted estrogens was significantly lower, ranging from 48 (11 beta-methylestradiol) to 2 (11 beta-methoxy-17 alpha-ethinylestradiol). Kidney DNA of hamsters treated with the four 17 alpha-ethinyl estrogens, when analyzed by 32P postlabeling assay, contained the same set of covalently modified nucleotides the formation of which had previously been found to precede estrogen-induced renal carcinogenesis in vivo. In contrast, relative rates of catechol estrogen formation by BALB/c 3T3 microsomes correlated with induction of morphological transformation of BALB/c 3T3 cells and decreased in the following order: 11 beta-methylestradiol greater than 17 alpha-ethinylestradiol greater than or equal to estradiol greater than 11 beta-ethylestradiol greater than 11 beta-methoxy-17 alpha-ethinylestradiol. The hormonal potencies of several estrogen derivatives studied by various assays did not correlate with in vivo carcinogenic or in vitro cell-transforming activities. It is concluded from these experiments that in cell culture catechol formation and morphological transformation are directly related. In vivo, aromatic hydroxylation of administered estrogens did not correlate with the incidence of estrogen-induced renal carcinoma in Syrian hamsters.
ISSN:	0008-5472 1538-7445