Chapter 6: Estrogen Metabolism by Conjugation

The involvement of estrogens in carcinogenic processes within estrogen-responsive tissues has been recognized for a number of years. Classically, mitogenicity associated with estrogen receptor-mediated cellular events was believed to be the mechanism by which estrogens contributed to carcinogenesis. Recently, the possibility that estrogens might contribute directly to mutagenesis resulting from DNA damage has been investigated. That damage is apparently a result of the formation of catechol estrogens that can be further oxidized to semiquinones and quinones. Those molecules represent reactive oxygen species and electrophilic molecules that can form depurinating DNA adducts, thus having the potential to result in permanent nucleotide mutation. Conjugation of parent estrogens to sulfate and glucuronide moieties; of catechol estrogens to methyl, sulfate, and glucuronide conjugates; and of catechol estrogen quinones to glutathione conjugates all represent potential "detoxification" reactions that may protect the cell from estrogen-mediated mitogenicity and mutagenesis. In this chapter, the biochemistry and molecular genetics of those conjugative reaction pathways are discussed. When applicable, the involvement of specific enzymatic isoforms is presented. Finally, the activity of many of these conjugative biotransformation reactions is subject to large interindividual variation--often due to the presence of common nucleotide polymorphisms within the genes encoding those enzymes. Functionally significant genetic polymorphisms that might contribute to variable conjugation of estrogens and catechol estrogens are also discussed.