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The influence of metabolism on the genotoxicity of catechol estrogens in three cultured cell lines
Author(s) -
Gerstner Silke,
Glasemann Dörte,
Pfeiffer Erika,
Metzler Manfred
Publication year - 2008
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.200700489
Subject(s) - genotoxicity , glucuronidation , catechol , catechol o methyl transferase , estrone , chemistry , metabolism , biochemistry , carcinogen , dna damage , dna , enzyme , microsome , hormone , toxicity , gene , allele , organic chemistry
Abstract The 2‐ and 4‐hydroxy metabolites of 17β‐estradiol (E2) and estrone (E1) are important for E2‐mediated carcinogenesis due to the formation of genotoxic ortho‐quinone metabolites. To assess the importance of metabolic conjugation for their genotoxicity, the DNA strand‐breaking activity of the four catechol estrogens was determined in three cell lines with different activities of catechol‐ O ‐methyltransferase (COMT) and UDP‐glucuronosyltransferase (UGT). Most DNA strand breaks were observed in V79 cells, which lack these metabolic activities. 2‐ and 4‐hydroxy‐E2 were 2.5 times more genotoxic than 2‐ and 4‐hydroxy‐E1. MCF‐7 cells exhibit COMT activity, and the incidence of DNA strand breaks decreased with increasing methylation; only the 4‐hydroxy metabolites of E1 and E2, which were poor substrates of COMT, exhibited low genotoxicity. HepG2 cells converted the catechol and methoxy metabolites of E2 to the respective E1 metabolites by 17β‐hydroxysteroid dehydrogenase (HSD). Moreover, methylation and glucuronidation took place. Only 4‐hydroxy‐E1 elicited a weak genotoxic response in these cells. The extensive metabolism in HepG2 cells is proposed to account for the failure of catechol estrogens to induce DNA strand breaks. Thus, metabolism by COMT and UGT and, to a minor extent, by HSD is a major determinant for the genotoxicity of catechol estrogens in target cells.