Tibolone is metabolized by the 3α/3β-hydroxysteroid dehydrogenase activities of the four human isozymes of the aldo–keto reductase 1C subfamily: inversion of stereospecificity with a Δ5(10)-3-ketosteroid

Ketosteroid substrates can bind in reverse orientation, with the D-ring at the base of the pocket instead of the A-ring.

“ketosteroid substrates can bind in reverse orientation so that the D-ring binds at the base of the pocket instead of the A-ring”

Hydroxysteroid product stereochemistry can be inverted by the ketosteroid being pushed across the pocket or bound upside down.

“stereochemistry of the hydroxysteroid product can be inverted by either the ketosteroid being pushed across the steroid pocket by steric forces or the ketosteroid can be bound upside down”

AKR1C1 and AKR1C2 form 3β-hydroxytibolone and are responsible for prodrug activation in peripheral tissues, where the 3β-hydroxymetabolite activates ERα/β.

“AKR1C1 and AKR1C2 form 3β-hydroxytibolone and are responsible for pro-drug activation in peripheral tissues where the 3β-hydroxymetabolite activates ERα/β.”

The same outcome for norethynodrel suggests that the 7α-methyl group in tibolone does not determine the stereochemical outcome.

“The same outcome is observed for the norethynodrel suggesting that the presence of the 7α-methyl group in tibolone does not determine the stereochemcial outcome.”

Formation of 3β-hydroxytibolone is preferred over 3α-hydroxytibolone because the 5(10)-ene and 17α-ethinyl group allow the steroid to flip at the active site relative to 5α-DHT.

“The formation of the 3β-hydroxymetabolite is preferred over the 3α-hydroxymetabolite because the presence of the 5(10)-ene and 17α-ethinyl group enables the steroid to be flipped over at the active-site relative to 5α-DHT.”

The mainly liver-specific AKR1C4 forms the 3α-hydroxy-metabolite, which is the major circulating tibolone metabolite.

“By contrast the mainly liver specific AKR1C4 forms the 3α-hydroxy-metabolite which is the major metabolite found in the circulation”

AKR1 enzymes are involved in the metabolism of tibolone, norethynodrel, dydrogesterone, budesonide and flunisolide.

“AKR1 enzymes are involved in the metabolism of tibolone and the progestins, norethynodrel and dydrogesterone (Table 4, Figure 6), as well as the synthetic glucocorticoids budesonide and flunisolide”