PMID- 12901862
OWN - NLM
STAT- MEDLINE
DCOM- 20030911
LR  - 20190612
IS  - 0006-291X (Print)
IS  - 0006-291X (Linking)
VI  - 308
IP  - 2
DP  - 2003 Aug 22
TI  - Inhibition of 11 beta-hydroxysteroid dehydrogenase type 2 by dithiocarbamates.
PG  - 257-62
AB  - Dithiocarbamates (DTCs), important therapeutic and industrial chemicals released 
      in high quantities into the environment, exhibit complex chemical and biological 
      activities. Here, we demonstrate an effect of DTCs on glucocorticoid action due 
      to inhibition of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) type 2, 
      converting cortisol to cortisone in the kidney, but not 11 beta-HSD1, catalyzing 
      the reverse reaction in liver and adipose tissue. Thus, DTCs may locally increase 
      active glucocorticoid concentrations. Preincubation with the DTC thiram abolished 
      11 beta-HSD2 activity, suggesting irreversible enzyme inhibition. The sulfhydryl 
      protecting reagent dithiothreitol blocked thiram-induced inhibition and NAD+ 
      partially protected 11 beta-HSD2 activity, indicating that DTCs act at the 
      cofactor-binding site. A 3D-model of 11 beta-HSD2 identified Cys90 in the 
      NAD(+)-binding site as a likely target of DTCs, which was supported by a 99% 
      reduced activity of mutant Cys90 to serine. The interference of DTCs with 
      glucocorticoid-mediated responses suggests a cautious approach in the use of DTCs 
      in therapeutic applications and in exposure to sources of DTCs such as cosmetics 
      and agricultural products by pregnant women and others.
FAU - Atanasov, Atanas G
AU  - Atanasov AG
AD  - Division of Nephrology and Hypertension, Department of Clinical Research, 
      University of Berne, Berne CH-3010, Switzerland.
FAU - Tam, Steven
AU  - Tam S
FAU - Rocken, Jens M
AU  - Rocken JM
FAU - Baker, Michael E
AU  - Baker ME
FAU - Odermatt, Alex
AU  - Odermatt A
LA  - eng
GR  - DK41841/DK/NIDDK NIH HHS/United States
GR  - HLOO4791/HL/NHLBI NIH HHS/United States
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  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Environmental Pollutants)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Thiocarbamates)
RN  - 0D771IS0FH (Thiram)
RN  - 0U46U6E8UK (NAD)
RN  - EC 1.1.- (Hydroxysteroid Dehydrogenases)
RN  - EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 2)
RN  - EC 1.1.1.146 (HSD11B2 protein, human)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - 11-beta-Hydroxysteroid Dehydrogenase Type 2
MH  - Amino Acid Substitution
MH  - Catalytic Domain/genetics
MH  - Cell Line
MH  - Cysteine/chemistry
MH  - Environmental Pollutants/toxicity
MH  - Enzyme Inhibitors/chemistry/*toxicity
MH  - Humans
MH  - Hydroxysteroid Dehydrogenases/*antagonists & inhibitors/chemistry/genetics
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Mutagenesis, Site-Directed
MH  - NAD/pharmacology
MH  - Recombinant Proteins/antagonists & inhibitors/chemistry/genetics
MH  - Thiocarbamates/chemistry/*toxicity
MH  - Thiram/pharmacology/toxicity
MH  - Transfection
EDAT- 2003/08/07 05:00
MHDA- 2003/09/13 05:00
CRDT- 2003/08/07 05:00
PHST- 2003/08/07 05:00 [pubmed]
PHST- 2003/09/13 05:00 [medline]
PHST- 2003/08/07 05:00 [entrez]
AID - S0006291X03013597 [pii]
AID - 10.1016/s0006-291x(03)01359-7 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2003 Aug 22;308(2):257-62. doi: 
      10.1016/s0006-291x(03)01359-7.