Metabolism of the synthetic progestogen norethynodrel by human ketosteroid reductases of the aldo–keto reductase superfamily

Human ketosteroid reductases of the aldo–keto reductase (AKR) superfamily, i.e. AKR1C1–4, are implicated in the biotransformation of synthetic steroid hormones. Norethynodrel (NOR, 17α-ethynyl-17β-hydroxy-estra-5(10)-en-3-one), the progestin component of the first marketed oral contraceptive, is known to undergo rapid and extensive metabolism to 3α- and 3β-hydroxymetabolites. The ability of the four human AKR1C enzymes to catalyze the metabolism of NOR has now been characterized. AKR1C1 and AKR1C2 almost exclusively converted NOR to 3β-hydroxy NOR, while AKR1C3 gave 3β-hydroxy NOR as the main product and AKR1C4 predominantly formed 3α-hydroxy NOR. Individual AKR1C enzymes also displayed distinct kinetic properties in the reaction of NOR. In contrast, norethindrone (NET), the Δ4-isomer of NOR and the most commonly used synthetic progestogen, was not a substrate for the AKR1C enzymes. NOR is also structurally identical to the hormone replacement therapeutic tibolone (TIB), except TIB has a methyl group at the 7α-position. Product profiles and kinetic parameters for the reduction of NOR catalyzed by each individual AKR1C isoform were identical to those for the reduction of TIB catalyzed by the respective isoform. These data suggest that the presence of the 7α-methyl group has a minimal effect on the stereochemical outcome of the reaction and kinetic behavior of each enzyme. Results indicate a role of AKR1C in the hepatic and peripheral metabolism of NOR to 3α- and 3β-hydroxy NOR and provide insights into the differential pharmacological properties of NOR, NET and TIB.

Figure optionsDownload as PowerPoint slideHighlights
► 3-Keto reduction of norethynodrel to 3α- or 3β-hydroxysteroids by AKR1C1–4.
► Distinct stereochemistry and kinetics with individual AKR1C isoforms.
► Similarity between norethynodrel and tibolone as substrates of AKR1C isoforms.
► Differential roles of AKR1Cs in hepatic and peripheral metabolism of norethynodrel.