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Kinetic studies on rabbit liver glucocorticoid 5alpha-reductase
K Kuhlmann1, H Bühler, V Ragosch
1Department of Obstetrics and Gynecology, Klinikum Benjamin Franklin, Free University of Berlin, Germany. kuhlmank@zedat-fu-berlin.de
Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme
|March 22, 2000
Summary
The liver enzyme 5alpha-reductase metabolizes 11-dehydro-glucocorticoids, limiting potential glucocorticosteroid (GCS) excess. This pathway, involving 5alpha-reductase type 1, balances GCS activation by 11beta-HSD1.
Area of Science:
- Biochemistry
- Endocrinology
- Enzymology
Background:
- Serum active glucocorticosteroids (GCS) are regulated by adrenal synthesis and hepatic activation via 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1).
- Understanding the role of other enzymes in 11-dehydro-glucocorticoid metabolism is crucial for comprehending GCS homeostasis.
Purpose of the Study:
- To evaluate the kinetic behavior of NADPH:delta 4-3-ketosteroid-5alpha-reductase (5alpha-reductase) in rabbit liver.
- To elucidate the interrelations between 5alpha-reductase and liver 11beta-HSD1 in GCS metabolism.
Main Methods:
- Kinetic properties of rabbit liver 5alpha-reductase were measured using a radioenzymatic assay.
- Enzyme kinetics were characterized based on protein, substrate, cosubstrate, and pH dependence.
- Michaelis-Menten parameters (Km and Vmax) were determined for 5alpha-reduced metabolites.
Main Results:
- Both 11-dehydrocorticosterone and corticosterone exhibited high affinity for 5alpha-reductase.
- Kinetic data, cosubstrate/pH dependence, and finasteride inhibition suggest 5alpha-reductase type 1 primarily controls 11-dehydrocorticosterone metabolism.
- 5alpha-reductase activity was identified as a significant pathway for deactivating 11-dehydro-glucocorticoids in the liver.
Conclusions:
- Hepatic 5alpha-reductase plays a key role in deactivating 11-dehydro-glucocorticoids, acting as a counterbalance to 11beta-HSD1-mediated activation.
- This metabolic pathway helps limit potential GCS excess at the hepatocyte level, regulating both corticosterone and 11-dehydrocorticosterone.
- The findings highlight the importance of 5alpha-reductase in maintaining glucocorticoid balance.