Studies on Biotransformation of STS 557

Abstract

Transformation of STS 557 (17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one) by female rat liver microsomes demonstrates a lower transformation rate in comparison with the analogous compound without 9-double bond: 17 alpha-cyanomethyl-19-nortestosterone, and the basic substance: 19-nortestosterone. 17 alpha-Cyanomethyl-estra-1, 3, 5(10), 9(11)-tetraene-3, 17 beta-diol, 17 alpha-cyanomethyl-11 beta, 17 beta-dihydroxy-estra-4, 9-dien-3-one, and tentatively 17 alpha-cyanomethyl-6 alpha, 17 beta-dihydroxy-estra-4, 9-dien-3-one were identified as metabolites. Microbial model investigations with species known to hydrogenate the 4-double bond in 4-en-3-oxo steroids stereospecifically to 5 alpha H- or 5 beta H-metabolites indicate 5 alpha-hydrogenation to be prevented in STS 557 by the 9-double bond, whereas 5 beta-hydrogenation is not affected. Isolation and characterization of metabolites from beagle dog and rat urine following administration of 3H-STS 557 revealed the following pathways of biotransformation: Hydroxylation in different positions of the steroid molecule, aromatization of ring A, hydrogenation of a double bond, simultaneous hydroxylation and hydrogenation, and alteration of the 17 alpha-side chain with loss of nitrogen.

Identification of bioactive products from environmental transformation of steroids

“…93 This compound (i.e., STS 433) was previously described as a product of DNG metabolism by the nitrile hydratase-containing microorganism Rhodococcus erythropolis. 93 Aromatic A was isolated at ~ 5% yield at pH 7, and formed at trace levels at pH 5. hereafter referred to as "Aromatic B", all agree with those of known DNG metabolite STS 825, 93,[96][97] which has also been identified as a product of DNG photolysis in acetonitrile. 98 Although the photolysis of DNG has previously been examined, its irradiation in organic solvent, which lead to some variation in product distribution relative to the results reported herein, is not environmentally relevant.…”

“…A-ring aromatization of DNG has been previously reported in microbial DNG biotransformation reactions and also can occur metabolically in humans and other mammals. 93,[96][97] In our photochemical systems, we speculate that Aromatic A (or STS 433) is generated from an initial photohydration step at C-10, followed by a fast thermal aromatization (i.e., dehydration and enolization). A similar acid-catalyzed aromatization was previously described for the synthesis of estrone and estradiol.…”

“…For example, 11β-hydroxydienogest is, in fact, a known DNG metabolite in microbes, mammals, and humans, previously identified as STS 749. [96][97][100][101] Prior investigations have revealed this metabolite to exhibit trace progestogenic activity equivalent to roughly 2% that of the parent DNG. [100][101] Thus, its formation via thermal rearrangement of Diene A presents a route to conserved progestogenic activity, particularly in slightly acidic surface waters (e.g., pH 5) where…”

Studies on the Biotransformation of the Progestagen Dienogest in the Rabbit *)

“…In the fields of progestagens it should made reference that the 3ß/5x-and 3x/5x-tetrahydrocompounds of norethisterone are efficient competitors for the estrogen cytosol receptor and might be responsible for the well documented estrogenic potency of norethisterone in vivo (Chavez et al, 1985). The Dienogest metabolite 17x-cyanomethyl-1, 3,5(10), 9(11)-estratetraen-3, 17ß-diol (Schubert et al, 1983) was found to, inhibit fertility in rats (Stölzner, not published), and this may contribute to the effects of Dienogest. It would be interesting to prove the effects of other Dienogest metabolites too, but their chemical preparation has proved highly complicated particularly if several biotransformation reactions have occurred.…”

“…Some principal features of Dienogest biotransformation which may be common to 4, 9-dien-3-oxo steroids generally could be derived from in vitro studies using rat liver microsomes (Schubert et al, 1983) and by the microbial transformation of Dienogest (Hobe et aL, 1982, Kaufmann et al, 1986. The 9-double bond obviously has a retarding effect on the hydrogenation of the 4-double bond and, if enzymic hydrogenation occurs, only compounds of the 5ßH series are formed (Schubert et al, 1983).…”