Reaction of Adenine with 6-Hydroxyestrogen 6-Sulfates: Model Compounds to Demonstrate Carcinogenesis by Estrogen.

Abstract

To examine carcinogenesis by estrogens, we investigated the reactivity of 6-hydroxyestrogen 6-sulfates. Two epimeric 6-sulfates, pyridinium 3-methoxyestra-1,3,5(10)-trien-6 alpha-yl sulfate (1) and its 6 beta-isomer (2), were synthesized as model compounds and reacted with adenine under mild conditions to give two common products in the ratios of approximately 3:1 and 5:1, respectively. The major product was identified as N6-[3-methoxyestra-1,3,5(10)-trien-6 beta-yl] adenine (10), accompanied with its 6 alpha-isomer (9), by comparison with synthetic specimens. These results imply that, in the metabolism of naturally occurring estrogens, hydroxylation at the C6-position and subsequent sulfoconjugation of the benzylic hydroxyl group may produce sulfates which react with DNA to initiate carcinogenesis.