scholarly journals Kinetic Studies of the Inhibition of a Human Liver 3.ALPHA.-Hydroxysteroid/Dihydrodiol Dehydrogenase Isozyme by Bile Acids and Anti-inflammatory Drugs.

1995 ◽  
Vol 18 (1) ◽  
pp. 9-12 ◽  
Author(s):  
Yoshiyuki MIYABE ◽  
Tetsuya AMANO ◽  
Yoshihiro DEYASHIKI ◽  
Akira HARA ◽  
Fumitake TSUKADA
Keyword(s):  
Bile Acids ◽  
Human Liver ◽  
Kinetic Studies ◽  
Dehydrogenase Isozyme ◽  
Dihydrodiol Dehydrogenase ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

scholarly journals Structural and functional comparison of two human liver dihydrodiol dehydrogenases associated with 3 α-hydroxysteroid dehydrogenase activity

1992 ◽  
Vol 282 (3) ◽  
pp. 741-746 ◽  
Author(s):  
Y Deyashiki ◽  
H Taniguchi ◽  
T Amano ◽  
T Nakayama ◽  
A Hara ◽  
...  
Keyword(s):  
Bile Acids ◽  
Dehydrogenase Activity ◽  
Human Liver ◽  
Hydrogen Transfer ◽  
Peptide Mapping ◽  
Reductase Activity ◽  
High Specificity ◽  
Hydroxysteroid Dehydrogenase ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Two monomeric dihydrodiol dehydrogenases with pI values of 5.4 and 7.6 were co-purified with androsterone dehydrogenase activity to homogeneity from human liver. The two enzymes differed from each other on peptide mapping and in their heat-stabilities; with respect to the latter the dihydrodiol dehydrogenase and 3 alpha-hydroxysteroid dehydrogenase activities of the respective enzymes were similarly inactivated. The pI 5.4 enzyme was equally active towards trans- and cis-benzene dihydrodiols, and towards (S)- and (R)-forms of indan-1-ol and 1,2,3,4-tetrahydronaphth-1-ol and oxidized the 3 alpha-hydroxy group of C19-, C21- and C24-steroids, whereas the pI 7.6 enzyme showed high specificity for trans-benzene dihydrodiol, (S)-forms of the alicyclic alcohols and C19- and C21-steroids. Although the two enzymes reduced various xenobiotic carbonyl compounds and the 3-oxo group of C19- and C21-steroids, and were A-specific in the hydrogen transfer from NADPH, only the pI 5.4 enzyme showed reductase activity towards 7 alpha-hydroxy-5 beta-cholestan-3-one and dehydrolithocholic acid. The affinity of the two enzymes for the steroidal substrates was higher than that for the xenobiotic substrates. The two enzymes also showed different susceptibilities to the inhibition by anti-inflammatory drugs and bile acids. Whereas the pI-5.4 enzyme was highly sensitive to anti-inflammatory steroids, showing mixed-type inhibitions with respect to indan-1-ol and androsterone, the pI 7.6 enzyme was inhibited more potently by non-steroidal anti-inflammatory drugs and bile acids than by the steroidal drugs, and the inhibitions were all competitive. These structural and functional differences suggest that the two enzymes are 3 alpha-hydroxysteroid dehydrogenase isoenzymes.

GLUCURONIDATION OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS: IDENTIFYING THE ENZYMES RESPONSIBLE IN HUMAN LIVER MICROSOMES

2005 ◽  
Vol 33 (7) ◽  
pp. 1027-1035 ◽  
Author(s):  
Gwendolyn E. Kuehl ◽  
Johanna W. Lampe ◽  
John D. Potter ◽  
Jeannette Bigler
Keyword(s):  
Human Liver ◽  
Liver Microsomes ◽  
Human Liver Microsomes ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Reduction of prostaglandin D2 to 9α,11β-prostaglandin F2 by a human liver 3α-hydroxysteroid/dihydrodiol dehydrogenase isozyme

1994 ◽  
Vol 1215 (1-2) ◽  
pp. 59-65 ◽  
Author(s):  
Hirotami Ohara ◽  
Toshihiro Nakayama ◽  
Yoshihiro Deyashiki ◽  
Akira Hara ◽  
Yoshiyuki Miyabe ◽  
...  
Keyword(s):  
Human Liver ◽  
Prostaglandin D2 ◽  
Dehydrogenase Isozyme ◽  
Dihydrodiol Dehydrogenase

scholarly journals Effect of indomethacin on bile acid-phospholipid interactions: implication for small intestinal injury induced by nonsteroidal anti-inflammatory drugs

2010 ◽  
Vol 298 (5) ◽  
pp. G722-G731 ◽  
Author(s):  
Yong Zhou ◽  
Elizabeth J. Dial ◽  
Rand Doyen ◽  
Lenard M. Lichtenberger
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Membrane Surface ◽  
Intestinal Injury ◽  
Disruptive Effect ◽  
Plasma Membrane Permeability ◽  
Small Intestinal Injury ◽  
Inflammatory Drugs ◽  
Small Intestinal ◽  
Anti Inflammatory

The injurious effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in the small intestine was not appreciated until the widespread use of capsule endoscopy. Animal studies found that NSAID-induced small intestinal injury depends on the ability of these drugs to be secreted into the bile. Because the individual toxicity of amphiphilic bile acids and NSAIDs directly correlates with their interactions with phospholipid membranes, we propose that the presence of both NSAIDs and bile acids alters their individual physicochemical properties and enhances the disruptive effect on cell membranes and overall cytotoxicity. We utilized in vitro gastric AGS and intestinal IEC-6 cells and found that combinations of bile acid, deoxycholic acid (DC), taurodeoxycholic acid, glycodeoxycholic acid, and the NSAID indomethacin (Indo) significantly increased cell plasma membrane permeability and became more cytotoxic than these agents alone. We confirmed this finding by measuring liposome permeability and intramembrane packing in synthetic model membranes exposed to DC, Indo, or combinations of both agents. By measuring physicochemical parameters, such as fluorescence resonance energy transfer and membrane surface charge, we found that Indo associated with phosphatidylcholine and promoted the molecular aggregation of DC and potential formation of larger and isolated bile acid complexes within either biomembranes or bile acid-lipid mixed micelles, which leads to membrane disruption. In this study, we demonstrated increased cytotoxicity of combinations of bile acid and NSAID and provided a molecular mechanism for the observed toxicity. This mechanism potentially contributes to the NSAID-induced injury in the small bowel.

scholarly journals Roles of the C-terminal domains of human dihydrodiol dehydrogenase isoforms in the binding of substrates and modulators: probing with chimaeric enzymes

1998 ◽  
Vol 336 (2) ◽  
pp. 429-436 ◽  
Author(s):  
Kazuya MATSUURA ◽  
Akira HARA ◽  
Yoshihiro DEYASHIKI ◽  
Harunori IWASA ◽  
Toshiyuki KUME ◽  
...  
Keyword(s):  
Amino Acids ◽  
Bile Acids ◽  
Wild Type ◽  
Terminal Sequence ◽  
Potent Inhibition ◽  
Highly Sensitive ◽  
Dihydrodiol Dehydrogenase ◽  
Inflammatory Drugs ◽  
Hydroxy Groups ◽  
Terminal Domains

Human liver dihydrodiol dehydrogenase (DD; EC 1.3.1.20) exists in isoforms (DD1, DD2 and DD4) composed of 323 amino acids. DD1 and DD2 share 98% amino acid sequence identity, but show lower identities (approx. 83%) with DD4, in which a marked difference is seen in the C-terminal ten amino acids. DD4 exhibits unique catalytic properties, such as the ability to oxidize both (R)- and (S)-alicyclic alcohols equally, high dehydrogenase activity for bile acids, potent inhibition by steroidal anti-inflammatory drugs and activation by sulphobromophthalein and clofibric acid derivatives. In this study, we have prepared chimaeric enzymes, in which we exchanged the C-terminal 39 residues between the two enzymes. Compared with DD1, CDD1-4 (DD1 with the C-terminal sequence of DD4) had increased kcat/Km values for 3α-hydroxy-5β-androstanes and bile acids of 3–9-fold and decreased values for the other substrates by 5–100-fold. It also became highly sensitive to DD4 inhibitors such as phenolphthalein and hexoestrol. Another chimaeric enzyme, CDD4-1 (DD4 with the C-terminal sequence of DD1), showed the same (S)-stereospecificity for the alicyclic alcohols as DD1, had decreased kcat/Km values for bile acids with 7β- or 12α-hydroxy groups by more than 120-fold and was resistant to inhibition by betamethasone. In addition, the activation effects of sulphobromophthalein and bezafibrate decreased or disappeared for CDD4-1. The recombinant DD4 with the His314 → Pro (the corresponding residue of DD1) mutation showed intermediate changes in the properties between those of wild-type DD4 and CDD4-1. The results indicate that the binding of substrates, inhibitors and activators to the enzymes is controlled by residues in their C-terminal domains; multiple residues co-ordinately act as determinants for substrate specificity and inhibitor sensitivity.

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