Role of metabolic activation in the transplacental carcinogenicity of diethylstilbestrol

Abstract

Metabolic studies have shown a variety of oxidative pathways in the biotransformation of the synthetic estrogen, diethylstilbestrol (DES). The metabolic intermediates are reactive electrophiles and bind covalently to proteins and nucleic acids. DES and some of its metabolites have proven to be genotoxic in several assays using mammalian cells. Oxidative metabolism of DES has also been shown in rodent fetuses and even in the ultimate target organ of DES transplacental carcinogenicity, the fetal genital tract. These findings imply that reactive metabolites may play a role in DES fetotoxicity, and several mechanisms accounting for the organotropism of DES transplacental carcinogenicity are proposed.