Effect of immunosuppressive and other drugs on the cortisol-cortisone shuttle in human kidney and liver.
BACKGROUND
Impaired 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) has been suggested in patients with hypertension or renal disease, where it may contribute to sodium retention and hypertension. 11beta-HSD1, which is expressed predominantly in liver and adipose tissue, influences glucose homeostasis and fat distribution by altering intracellular cortisol (F) concentrations. We tested immunosuppressive drugs that cause hypertension, and substances that interfere with steroidogenesis or influence glucose homeostasis for their ability to influence the inhibition of 11beta-HSD isozymes.


METHODS
For inhibition experiments, we used microsomes prepared from unaffected parts of human liver segments and resected human kidney cortex because of hepatocarcinoma or renal cell cancer. The inhibitory potency of several compounds was evaluated in concentrations from 10(-9)-10(-5) mol/l.


RESULTS
Only sirolimus, but not cyclosporine A, tacrolimus, mycophenolate mofetil, or azathioprine showed a slight inhibition of 11beta-HSD2 activity. None of the drugs that inhibit steroidogenesis (suramine, mitotane, etomidate, and aminogluthethimide) or steroid metabolism (rifampicine) influenced 11beta-HSDs, nor did ginsenoides Re, Rc, and Rb1. Among sulfonylureas, only gliclazide decreased significantly 11beta-HSD1 activity.


CONCLUSIONS
Increased blood pressure due to immunosuppressive drugs is probably not caused by direct inhibition of 11beta-HSD2. An additional glucose lowering effect of sulfonylurea gliclazide may be due to its ability to inhibit 11beta-HSD1.
Quinkler
M
M
Clinical Endocrinology, Department of Internal Medicine, Center for Gastroenterology, Heptology and Endocrinology, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany. marcus.quinkler@charite.de
Jussli
J
J
Bähr
V
V
Pfeiffer
A F H
AF
Lepenies
J
J
Diederich
S
S
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport / Q000187:drug effects; D002229:Carbenoxolone / Q000494:pharmacology; D003348:Cortisone / Q000378:metabolism*; D005260:Female; D006034:Glycyrrhetinic Acid / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D013256:Steroids / Q000378:metabolism
D007166:Immunosuppressive Agents; D004364:Pharmaceutical Preparations; D013256:Steroids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone; D006034:Glycyrrhetinic Acid; D003348:Cortisone; D006854:Hydrocortisone