TY - JOUR
T1 - The O6-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol
T2 - Implications for estrogen-induced carcinogenesis
AU - Roy, Deodutta
AU - Weisz, Judith
AU - Liehr, Joachim G.
N1 - Funding Information:
The expert assistance of Ms Rosalba Ortiz and Ms Gayla Clark in the preparation of the text and of Mr Mark L.Winter in the preparation of the illustrations is gratefully acknowledged. Supported by the National Cancer Institute, National Institutes of Health, Grants CA43232, CA43233 and CA44069 (to J.G.L.), the American Cancer Society, Grant RD 2528 and by the Council for Tobacco Research, Grant no. 2339 (to J.W.).
PY - 1990/3
Y1 - 1990/3
N2 - O-Methylation of catecholestrogens catalyzed by catechol-O-methyltransferase provides a major route for the rapid metabolic clearance of these steroids. However, the metabolic clearance rate of 4-hydroxyestradiol (4-OH-E2) is considerably lower than that of 2-hydroxyestradiol, although 2- and 4-hydroxycatecholestrogens (2- and 4-OH-CE) have similar apparent affinities for the enzyme. To determine the reason for this apparent paradox we have examined whether the efficiency of O-methylation of 4-OH-E2 could be affected by other catecholestrogens or their O-methyl ethers. The ratio of 4-methoxyestradiol:4-hydroxyestradiol 3-methyl ether was 2.6 at pH 8.5, the pH optimum for the reaction. The O-methylation of 4-OH-E2 (apparent Km 10 μM) was inhibited by 2-hydroxyestradiol (2-OH-E2) but not by 2- or 4-methoxyestrogens. The values for Km, Vmax as well as the slope for the methylation of 4-OH-E2 were altered by 2-OH-E2 indicating a mixed inhibition. The inhibition constant for the intercept 1/V'max versus 2-OH-E2 concentrations and the inhibition constant for the slope versus 2-OH-E2 concentrations were 35 and 5.7 μM, respectively. The inhibition of O-methylation of 4-OH-E2 by 2-OH-E2 increased with the pH. In target tissues of the carcinogenic action of estrogens such as the rat pituitary, hamster kidney, or mouse uterus in which 2- and 4-OH-CE are both generated in almost equal amounts, the inactivation of 4-OH-CE by O-methylation may be impeded. Consequently, 4-OH-E2 would remain available as substrate for redox cycling, generation of active radicals and DNA damage.
AB - O-Methylation of catecholestrogens catalyzed by catechol-O-methyltransferase provides a major route for the rapid metabolic clearance of these steroids. However, the metabolic clearance rate of 4-hydroxyestradiol (4-OH-E2) is considerably lower than that of 2-hydroxyestradiol, although 2- and 4-hydroxycatecholestrogens (2- and 4-OH-CE) have similar apparent affinities for the enzyme. To determine the reason for this apparent paradox we have examined whether the efficiency of O-methylation of 4-OH-E2 could be affected by other catecholestrogens or their O-methyl ethers. The ratio of 4-methoxyestradiol:4-hydroxyestradiol 3-methyl ether was 2.6 at pH 8.5, the pH optimum for the reaction. The O-methylation of 4-OH-E2 (apparent Km 10 μM) was inhibited by 2-hydroxyestradiol (2-OH-E2) but not by 2- or 4-methoxyestrogens. The values for Km, Vmax as well as the slope for the methylation of 4-OH-E2 were altered by 2-OH-E2 indicating a mixed inhibition. The inhibition constant for the intercept 1/V'max versus 2-OH-E2 concentrations and the inhibition constant for the slope versus 2-OH-E2 concentrations were 35 and 5.7 μM, respectively. The inhibition of O-methylation of 4-OH-E2 by 2-OH-E2 increased with the pH. In target tissues of the carcinogenic action of estrogens such as the rat pituitary, hamster kidney, or mouse uterus in which 2- and 4-OH-CE are both generated in almost equal amounts, the inactivation of 4-OH-CE by O-methylation may be impeded. Consequently, 4-OH-E2 would remain available as substrate for redox cycling, generation of active radicals and DNA damage.
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U2 - 10.1093/carcin/11.3.459
DO - 10.1093/carcin/11.3.459
M3 - Article
C2 - 2311190
AN - SCOPUS:0025099288
SN - 0143-3334
VL - 11
SP - 459
EP - 462
JO - Carcinogenesis
JF - Carcinogenesis
IS - 3
ER -