Metabolic activation of carcinogenic diethylstilbestrol in rodents and humans

Area of Science:

• Pharmacology
• Toxicology
• Metabolism Studies

Background:

• Diethylstilbestrol (DES) is a synthetic estrogen with known health implications.
• Understanding its in vivo biotransformation is crucial for assessing its toxicological profile.

Purpose of the Study:

• To investigate the in vivo biotransformation pathways of diethylstilbestrol (DES).
• To identify and characterize urinary and biliary metabolites of DES in Wistar rats and Syrian golden hamsters.
• To compare species differences in DES metabolism between humans and rats.

Main Methods:

• Radio-gas-liquid chromatography (radio-GLC) was employed.
• Gas chromatography-mass spectrometry (GLC-MS) was utilized.
• Both radioactively and deuterium-labeled DES were used for tracing.

Main Results:

• Identified dienestrol and various hydroxy/methoxy derivatives of dienestrol and DES in rat and hamster urine and bile.
• Confirmed 4'-hydroxypropiophenone as a rat urinary metabolite, supporting an epoxide-diol pathway for dienestrol formation.
• Found dienestrol and hydroxy dienestrol as major human urinary metabolites, with notable species-specific differences in excretion routes and metabolite patterns compared to rats.

Conclusions:

• The study elucidated key in vivo biotransformation products of DES in animal models.
• Identified metabolites suggest potential proximate carcinogens due to their electrophilic reactivity.
• Significant species differences in DES metabolism highlight the importance of considering human-specific pathways.