PMID- 8319583
OWN - NLM
STAT- MEDLINE
DCOM- 19930803
LR  - 20071114
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 133
IP  - 1
DP  - 1993 Jul
TI  - Structure and function of the hepatic form of 11 beta-hydroxysteroid 
      dehydrogenase in the squirrel monkey, an animal model of glucocorticoid 
      resistance.
PG  - 368-75
AB  - Both cortisol and aldosterone bind to and activate the mineralocorticoid 
      receptor. Cortisol concentrations are generally 100- to 200-fold higher than 
      aldosterone concentrations, yet mineralocorticoids clearly exert effects 
      different from glucocorticoids. One hypothesis is that 11 beta-hydroxysteroid 
      dehydrogenase (11 beta-HSD), which converts cortisol to biologically inactive 
      cortisone, protects the mineralocorticoid receptor from cortisol. The circulating 
      concentrations of cortisol in the squirrel monkey are 20- to 50-fold higher than 
      human cortisol concentrations, yet this animal has no evidence of glucocorticoid 
      or mineralocorticoid excess. We used this experiment of nature to test the 
      hypotheses that the known (hepatic) form of 11 beta-HSD protects renal 
      mineralocorticoid receptors from the action of cortisol and that it modulates 
      glucocorticoid concentrations in target tissues. Using a long oligonucleotide 
      based on the rat sequence, we cloned the squirrel monkey 11 beta-HSD 
      complementary DNA and gene. The encoded monkey amino acid sequence is 75% and 91% 
      identical to the corresponding rat and human sequences, respectively. The tissue 
      abundance of the messenger RNA for the monkey enzyme was similar to or less than 
      that seen for the rat and human enzymes. Both the monkey and human 11 beta-HSD 
      complementary DNAs were cloned into an expression vector and used to transfect 
      cultures of Chinese hamster ovary cells. Both vectors were transcribed and 
      translated into equivalent amounts of 11 beta-HSD enzyme. The monkey enzyme was 
      slightly more efficient than the human enzyme in converting [3H]cortisol to 
      cortisone, and estimates of the Michaelis-Menten constant and maximum velocity of 
      both enzymes are similar. These data indicate that the abundance and activity of 
      the hepatic form of 11 beta-HSD are insufficient to inactivate the very high 
      concentrations of cortisol in the squirrel monkey, suggesting that this form of 
      11 beta-HSD does not defend the mineralocorticoid receptor or protect tissues 
      from high cortisol concentrations. Rather, this enzyme appears to favor 
      conversion of cortisone to cortisol, thus maximizing tissue concentrations of 
      cortisol to overcome glucocorticoid resistance associated with a 50% reduction in 
      glucococorticoid receptors.
FAU - Moore, C C
AU  - Moore CC
AD  - Department of Pediatrics, University of California San Francisco 94143-0978.
FAU - Mellon, S H
AU  - Mellon SH
FAU - Murai, J
AU  - Murai J
FAU - Siiteri, P K
AU  - Siiteri PK
FAU - Miller, W L
AU  - Miller WL
LA  - eng
SI  - GENBANK/L09679
SI  - GENBANK/L09680
SI  - GENBANK/L09681
SI  - GENBANK/L09682
SI  - GENBANK/L09683
SI  - GENBANK/L16554
SI  - GENBANK/L16555
SI  - GENBANK/L16556
SI  - GENBANK/S63400
SI  - GENBANK/S67456
GR  - DK27970/DK/NIDDK NIH HHS/United States
GR  - DK37922/DK/NIDDK NIH HHS/United States
GR  - DK42154/DK/NIDDK NIH HHS/United States
GR  - etc.
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Glucocorticoids)
RN  - 0 (RNA, Messenger)
RN  - 9007-49-2 (DNA)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenases)
SB  - IM
MH  - 11-beta-Hydroxysteroid Dehydrogenases
MH  - Amino Acid Sequence
MH  - Animals
MH  - Base Sequence
MH  - CHO Cells
MH  - Cloning, Molecular
MH  - Cricetinae
MH  - DNA/chemistry/genetics
MH  - Drug Resistance
MH  - Glucocorticoids/*pharmacology
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/*chemistry/genetics/*metabolism
MH  - Liver/*enzymology
MH  - Molecular Sequence Data
MH  - RNA, Messenger/analysis
MH  - Saimiri
MH  - Tissue Distribution
MH  - Transfection
EDAT- 1993/07/01 00:00
MHDA- 1993/07/01 00:01
CRDT- 1993/07/01 00:00
PHST- 1993/07/01 00:00 [pubmed]
PHST- 1993/07/01 00:01 [medline]
PHST- 1993/07/01 00:00 [entrez]
AID - 10.1210/endo.133.1.8319583 [doi]
PST - ppublish
SO  - Endocrinology. 1993 Jul;133(1):368-75. doi: 10.1210/endo.133.1.8319583.