Metabolism of [14C]diethylstilboestrol epoxide by rat liver in vitro

Abstract

1. The trans-epoxide of diethylstilboestrol and its pinacolone were synthesized chemically and the pinacolone shown to be formed from the epoxide by a non-enzymic process. 2. [14C]Diethylstiboestrol epoxide was converted by rat liver microsomal fraction into 4'-hydroxypropiophenone by a new type of cleavage reaction involving mono-oxygenase. Conditions for the formation of this metabolite and also water-soluble products were investigated together with the effect of inhibitors. A sex-difference in the conversion of diethylstilboestrol epoxide into 4'-hydroxypropiophenone and to polar and water-soluble products was observed. 3. Diethylstilboestrol epoxide was found to be a relatively stable compound that did not form a glutathione conjugate readily without further microsomal activation. A purified preparation of epoxide hydratase did not enhance its rate of conversion into the pinacolone. 4. Diethylstilboestrol epoxide was found to have about one-tenth the oestrogenic activity of diethylstilboestrol as measured by the increase in uterine weight or the induction of peroxidase in immature rat uteri. It was inactive as a mutagen when tested for its ability to inhibit bacteriophage phi X174 DNA viral replication. 5. The possible role of diethylstilboestrol epoxide as an intermediate in the metabolism of diethylstilboestrol and in mediating the harmful effects of this synthetic estrogen is discussed.

Metabolite V, an epoxide species is a minor circulating metabolite in humans following a single oral dose of deflazacort

“…11 However, chemically and metabolically stable epoxides that are less reactive or nonreactive to epoxide hydrolase, resistant to nucleophilic attack or excreted as stable metabolites, have been reported. [12][13][14][15] This study and an earlier work from others 8 which found that 1,2-epoxy-3-OH-21-desDFZ (Metabolite V) is a stable metabolite as evidenced by successful isolation from human urine for structure elucidation;…”

“…The epoxides can be endogenous intermediates that are natural signaling molecules such as epoxyeicosatrienoic acids that are vasodilators and can influence both renal function and peripheral vascular tone and are also involved in the long‐term control of blood pressure 9 ; epoxides can be toxic, such as aflatoxin B1 exo‐8,9‐epoxide that can react with guanine in DNA to cause DNA damage 10 ; or like carbamazepine‐10,11‐epoxide, they can be pharmacologically active but toxic beyond certain level 11 . However, chemically and metabolically stable epoxides that are less reactive or nonreactive to epoxide hydrolase, resistant to nucleophilic attack or excreted as stable metabolites, have been reported 12‐15 . This study and an earlier work from others 8 which found that 1,2‐epoxy‐3‐OH‐21‐desDFZ (Metabolite V) is a stable metabolite as evidenced by successful isolation from human urine for structure elucidation; the absence of downstream metabolites, for example, epoxide hydrolysis products or glutathione adducts in the circulation may also suggest that 1,2‐epoxy‐3‐OH‐21‐desDFZ be metabolically stable and less reactive toward nucleophiles.…”

“…Proposed metabolic pathways for deflazacort following a single oral administration in healthy male human subjects vascular tone and are also involved in the long-term control of blood pressure 9 ; epoxides can be toxic, such as aflatoxin B1 exo-8,9-epoxide that can react with guanine in DNA to cause DNA damage10 ; or like carbamazepine-10,11-epoxide, they can be pharmacologically active but toxic beyond certain level. 11 However, chemically and metabolically stable epoxides that are less reactive or nonreactive to epoxide hydrolase, resistant to nucleophilic attack or excreted as stable metabolites, have been reported [12][13][14][15]. This study single oral dose.…”

“…500 μL chloroform-d3 for NMR analysis. All NMR experiments were collected on a Bruker 500 MHz spectrometer (Bruker BioSpin) operating at 500 MHz for 1 H and 125 MHz for13 C equipped with a 5 mm QNP probe. 1D 1 H-and 13 C-NMR and 2D heteronuclear single quantum coherence spectrometry (HSQC) data were collected at room temperature.…”