Abstract
In man and in rodents the hepatic 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is a functional oxidoreductase preferring NADP+/NADPH as cosubstrates. In contrast, the renal isoenzyme (11ß-HSD2) mediates in vivo only oxidation of natural glucocorticoids (GK) with NAD+ as cosubstrate. It is widely accepted that the function of the renal 11ß-HSD2 is the protection of mineralocorticoid (MC) receptors from high cortisol concentrations by inactivating cortisol to cortisone, thus prohibiting cortisol access to the MC receptor, which binds aldosterone and cortisol with similar affinity. The function of the hepatic 11ß-HSD1 is not yet well understood but it is thought that it plays a pivotal role in regulating the intracellular level of active GK.
We have recently characterized the 11ß-HSD isoenzymes in the guinea pig liver and kidney (Quinkler et al. 1997 J Endocrinol). In this work we investigated the in vivo effects of corticotropin (ACTH) on 11ß-HSDs in these organs and furthermore characterized the 11ß-HSD isoenzymes in homogenates of other tissues.
Guinea pigs were treated with ACTH (twice daily injections of 10 IU depot ACTH1-24 for three days) and saline respectively. Tissue slices of liver and kidney were incubated with 3H-labeled cortisol or cortisone, and the conversion of substrate to product was measured by thin layer chromatography. Furthermore different plasma steroid concentrations as well as urinary cortisol metabolites were measured by high pressure liquid chromatography or radioimmunoassay respectively.
Then homogenates of different guinea pig tissues (adrenal gland, kidney, lung, heart, liver, colon) were incubated with 3H-labeled cortisol or cortisone and cosubstrate (NAD/H, NADP/H) and the conversion of substrate to product measured as described above.
Three days of in vivo ACTH treatment significantly increased the reductase activity in liver (50,2% vs. 70,3% conversion) and kidney slices (39,6% vs. 56,8% conversion). At the same time oxidase activity was significantly decreased in both liver (33,7% vs. 23,9%) and kidney slices (33,9% vs. 28,6%). Furthermore 11ß-HSD1 activity assessed by measurement of the urinary ratio of tetrahydrocortisol [THF] + 5?-THF /tetrahydrocortisone was significantly increased after ACTH treatment compared to the control group.
Plasma levels of cortisol, cortisone, progesterone, 17-OH-progesterone and androstendione increased significantly following in vivo ACTH treatment.
In homogenates we could show clear-cut activity of 11ßHSD1 in liver > kidney > adrenal > lung and activity of 11ßHSD2 in kidney > adrenal > colon > lung > heart.
In conclusion we have shown that the stress adaptation of the guinea pig is not solely caused by increased adrenal secretion of cortisol but also through an increased 11ßHSD1 activity in liver and kidney. Therefore, liver and kidney might contribute to stress adaptation in an endocrine fashion, whereas other organs expressing 11ßHSD1 might regulate their needs for cortisol in an autocrine way. |
