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The oxidative metabolism of estrogens by mammalian liver

University of British Columbia

The main problem of estrogen metabolism studied has been to determine the nature of the water-soluble products formed from estrone-16-C¹⁴ by rat liver preparations. Comparative studies were carried out in the guinea pig. Three types of water-soluble metabolites were demonstrated, namely, protein-bound derivatives, glucosiduronate conjugates, and unidentified products which were not bound to protein and were not hydrolysed by 2N HC1. The water-soluble metabolites formed on incubating rat or guinea pig liver microsomes with estrone-16-C¹⁴ in the presence of NADPH and oxygen consisted of protein-bound material, some unknown derivatives, but virtually no simple conjugates. Incubation with the rat liver 8000 x g supernatant fraction resulted largely in conversion of the estrogen to the unknown water-soluble end-products, while in contrast, this liver fraction from guinea pig gave rise mainly to glucosiduronates. In the presence of UDPGA, both rat and guinea pig liver microsomes converted estrone-16-C¹⁴ to glucosiduronate conjugates, but this did not occur with the rat liver 8000 x g supernatant fraction. Estradiol-17β-16-C¹⁴and stilbestrol-C¹⁴ behaved similarly to estrone-16-C¹⁴. In the rat, in vivo, the bulk of the urinary water-soluble derivatives of estrone were of unknown nature, while in the guinea pig, glucosiduronate conjugation predominated. The problem was also studied by a different approach. Various compounds having structural features similar to estrone were tested for their ability to inhibit the formation of water-soluble metabolites from this estrogen by rat liver microsomes. It was found that 2-hydroxyestrone, 2-hydroxyestradiol-17β and equilenin were potent inhibitors, while those estrogens which had an oxygen function at C-6 or C-16, as well as the 17β-glucosiduronates and non-phenolic steroids tested were inactive. The synthetic estrogens, stilbestrol and hexestrol, both inhibited the reaction, but their non-estrogenic analogues had no effect. A group of benzoquinones, naphthoquinones and ortho- and para-hydroxylated phenols proved to be powerful inhibitors, whereas anthraquinones and meta-hydroxy-lated phenols showed no activity. In kinetic studies, 2-hydroxyestrone, equilenin, and stilbestrol appeared to act as competitive inhibitors, but menadione gave a mixed type of inhibition.

Text

2011-10-20

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http://hdl.handle.net/2429/38139

Biochemistry and Molecular Biology

University of British Columbia

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