Carcinogenesis, Vol 19, 1307-1312, Copyright © 1998 by Oxford University Press
J Weisz, G Fritz-Wolz, GA Clawson, CM Benedict, C Abendroth and CR Creveling
Catecholestrogens are postulated to contribute to carcinogenesis by causing
DNA damage mediated by reactive oxygen species generated during redox
cycling between catechol and quinone estrogens, and by quinone estrogens
that can form depurinating adducts. The above hypothesis is based
principally on studies of the cancers that develop in renal cortex of
hamsters treated with primary estrogens: Hamster kidney can catalyze 2- and
4-hydroxylation of estrogens and support their redox cycling, and the
kidneys of estradiol-treated hamsters show evidence of oxidative cellular
and DNA damage. Here we used immunocytochemisty to test the postulate that
catechol-O-methyltransferase (COMT), the enzyme that can prevent oxidation
of catecholestrogens to their quinone derivatives, would be induced in
renal cortex of hamsters treated with estradiol or ethinyl estradiol. In
kidneys of control hamsters, COMT was localized in cytoplasm of epithelial
cells of proximal convoluted tubules, predominantly in the juxtamedullary
region where the estrogen- induced cancers arise. After 2- or 4-weeks of
treatment with either estrogen, COMT was seen in epithelial cells of
proximal convoluted tubules throughout the cortex, and many cells also
showed intense nuclear COMT immunoreactivity. Estradiol-induced renal
cancers were negative for COMT, but were surrounded by tubules with intense
cytoplasmic and nuclear immunostaining. The nucleus-associated COMT was
shown by immunoblot analysis to be the soluble form of the enzyme. Using
reverse transcription-polymerase chain reaction amplification, hamster
kidney COMT was shown to lack the putative nuclear localization signal
sequence present in human COMT. A second phase II enzyme, CuZn- superoxide
dismutase (CuZnSOD), was shown by immunocytochemistry to remain
extranuclear in proximal convoluted tubules of estrogen-treated hamsters,
which indicates entry of COMT into the nucleus to be selective. The
findings are consistent with the catechol/quinone estrogen hypothesis of
estrogen-induced cancer, while the translocation of the enzyme to the
nucleus following estrogen treatment suggests a response to a threat to the
genome by electrophilic products of catechols.
ARTICLES
Induction of nuclear catechol-O-methyltransferase by estrogens in hamster kidney: implications for estrogen-induced renal cancer
Department of Obstetrics and Gynecology, M.S. Hershey Medical Center of the Pennsylvania State University, Hershey 17033, USA.
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