Catechol-O-methyltransferase: Factors Relating to the Carcinogenic Potential of Catecholestrogens

Abstract

Abstract Catechol−O−methyltransferase (COMT) catalyzes the transfer of the methyl group on the sulfonium moiety of the co−substrate S−adenosylmethione to one of the hydroxyl groups of most catechols. The catechols, 2−hydroxy− and 4−hydroxyestradiol are rapidly O−methylated and do not accumulate in tissues. Failure of O−methylation resulting in an accumulation of hydroxyestradiols, could result in their participation in redox cycling though their quinone forms and lead to the generation of superoxide radical, DNA damage, and carcinogenesis. It has been proposed that this redox cycle may be operant in tissues with inherently low levels of COMT as in the Syrian hamster kidney. Here catechol estrogen levels may exceed the local capacity for O−methylation. Of consideration are cell types like the epithelia of the uterine lumen or mammary ducts, where COMT activity changes from very low levels to elevated levels in response to hormonal stimulation. In this report the cellular distribution and activity of COMT are discussed in relationship to the potential role of catechol estrogens as endogenous carcinogens.