scholarly journals Selective inhibition of mitochondrial 27-hydroxylation of bile acid intermediates and 25-hydroxylation of vitamin D3 by cyclosporin A

1993 ◽  
Vol 293 (1) ◽  
pp. 203-206 ◽  
Author(s):  
H Dahlbäck-Sjöberg ◽  
I Björkhem ◽  
H M Princen
Keyword(s):  
Bile Acid ◽  
Cyclosporin A ◽  
Chenodeoxycholic Acid ◽  
Vitamin D3 ◽  
Kinetic Studies ◽  
Selective Inhibition ◽  
Acid Synthesis ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Alpha 7

It was demonstrated recently that cyclosporin A blocks bile acid synthesis in cultured rat and human hepatocytes by specific inhibition of chenodeoxycholic acid formation. The site of inhibition was found to be the 27-hydroxylation of cholesterol catalysed by the liver mitochondrial 27-hydroxylase [Princen, Meijer, Wolthers, Vonk and Kuipers (1991) Biochem J. 275, 501-505]. In this paper the mechanism by which cyclosporin A blocks mitochondrial 27-hydroxylation was further investigated. It is shown that cyclosporin A inhibited 27-hydroxylation of bile acid intermediates, depending on their polarity. In isolated rat liver mitochondria, 27-hydroxylation of cholesterol was dose-dependently blocked by the drug, giving half-maximal inhibition at 4 microM, whereas 27-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol was not affected. A similar observation was made using electrophoretically homogeneous cytochrome P-450(27) isolated from rabbit liver mitochondria, excluding the possibility that cyclosporin A interfered with transport of substrates into the mitochondrion. Kinetic studies showed that inhibition of the 27-hydroxylation of cholesterol by cyclosporin A was of a non-competitive type. The drug also inhibited the 25-hydroxylase activity towards vitamin D3, catalysed by the same enzyme preparation, to the same extent as 27-hydroxylation of cholesterol. These results suggest that cyclosporin A may interfere with binding of cholesterol, but not of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol, to the active site of the enzyme. These data provide an explanation for the selective inhibition of chenodeoxycholic acid synthesis.

scholarly journals Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

1991 ◽  
Vol 275 (2) ◽  
pp. 501-505 ◽  
Author(s):  
H M Princen ◽  
P Meijer ◽  
B G Wolthers ◽  
R J Vonk ◽  
F Kuipers
Keyword(s):  
Bile Acid ◽  
Cyclosporin A ◽  
Bile Acids ◽  
Chenodeoxycholic Acid ◽  
Alternative Pathway ◽  
Rat Hepatocytes ◽  
Acid Synthesis ◽  
Liver Mitochondria ◽  
Bile Acid Synthesis ◽  
Rat Liver Mitochondria

Bile acid synthesis, determined by conversion of [4-14C]cholesterol into bile acids in rat and human hepatocytes and by measurement of mass production of bile acids in rat hepatocytes, was dose-dependently decreased by cyclosporin A, with 52% (rat) and 45% (human) inhibition of 10 microM. The decreased bile acid production in rat hepatocytes was due only to a fall in the synthesis of beta-muricholic and chenodeoxycholic acids (-64% at 10 microM-cyclosporin A), with no change in the formation of cholic acid. In isolated rat liver mitochondria, 26-hydroxylation of cholesterol was potently inhibited by the drug (concn. giving half-maximal inhibition = 4 microM). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.

scholarly journals Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

2021 ◽  
Author(s):  
Akihiko Kimura ◽  
Tatsuki Mizuochi ◽  
Hajime Takei ◽  
Akira Ohtake ◽  
Jun Mori ◽  
...  
Keyword(s):  
Bile Acid ◽  
Chenodeoxycholic Acid ◽  
Acid Treatment ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Term Outcome ◽  
Long Term Outcome

The alterations in the energy linked properties induced in rat liver mitochondria by acetylsalycilate are prevented by cyclosporin A or Mg2+

1995 ◽  
Vol 50 (4) ◽  
pp. 497-500 ◽  
Author(s):  
Carla Biban ◽  
Vinicio Tassani ◽  
Antonio Toninello ◽  
Dagmar Siliprandi ◽  
Noris Siliprandi
Keyword(s):  
Cyclosporin A ◽  
Rat Liver ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria

scholarly journals The control of isocitrate oxidation by rat liver mitochondria

1969 ◽  
Vol 114 (2) ◽  
pp. 215-225 ◽  
Author(s):  
D. G. Nicholls ◽  
P. B. Garland
Keyword(s):  
Respiratory Chain ◽  
Rat Liver ◽  
Isocitrate Dehydrogenase ◽  
Adenine Nucleotides ◽  
Kinetic Studies ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Kinetic Properties ◽  
Dependent Inhibition ◽  
Nad 4

1. The factors capable of affecting the rate of isocitrate oxidation in intact mitochondria include the rate of isocitrate penetration, the activity of the NAD-specific and NADP-specific isocitrate dehydrogenases, the activity of the transhydrogenase acting from NADPH to NAD+, the rate of NADPH oxidation by the reductive synthesis of glutamate and the activity of the respiratory chain. A quantitative assessment of these factors was made in intact mitochondria. 2. The kinetic properties of the NAD-specific and NADP-specific isocitrate dehydrogenases extracted from rat liver mitochondria were examined. 3. The rate of isocitrate oxidation through the respiratory chain in mitochondria with coupled phosphorylation is approximately equal to the maximal of the NAD-specific isocitrate dehydrogenase but at least ten times as great as the transhydrogenase activity from NADPH to NAD+. 4. It is concluded that the energy-dependent inhibition of isocitrate oxidation by palmitoylcarnitine oxidation is due to an inhibition of the NAD-specific isocitrate dehydrogenase. 5. Kinetic studies of NAD-specific isocitrate dehydrogenase demonstrated that its activity could be inhibited by one or more of the following: an increased reduction of mitochondrial NAD, an increased phosphorylation of mitochondrial adenine nucleotides or a fall in the mitochondrial isocitrate concentration. 6. Uncoupling agents stimulate isocitrate oxidation by an extent equal to the associated stimulation of transhydrogenation from NADPH to NAD+. 7. A technique is described for continuously measuring with a carbon dioxide electrode the synthesis of glutamate from isocitrate and ammonia.

Poly(adenylic acid) synthesis in isolated rat liver mitochondria

Biochemistry ◽  
1976 ◽  
Vol 15 (23) ◽  
pp. 5046-5052 ◽  
Author(s):  
Kathleen M. Rose ◽  
Samson T. Jacob
Keyword(s):  
Rat Liver ◽  
Acid Synthesis ◽  
Liver Mitochondria ◽  
Rat Liver Mitochondria ◽  
Isolated Rat Liver ◽  
Adenylic Acid ◽  
Isolated Rat

scholarly journals Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

2005 ◽  
Vol 280 (16) ◽  
pp. 15579-15586 ◽  
Author(s):  
Victor V. Lemeshko ◽  
Mauricio Arias ◽  
Sergio Orduz
Keyword(s):  
Membrane Potential ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Liver Mitochondria ◽  
Peptide Sequence ◽  
Rat Liver Mitochondria ◽  
Tryptophan Residue ◽  
Inner Membrane

Bacillus thuringiensissubsp.medellinis known to produce the Cry11Bb protein of 94 kDa, which is toxic for mosquito larvae due to permeabilization of the plasma membrane of midgut epithelial cells. Earlier we found that a 2.8-kDa novel peptide BTM-P1, which was artificially synthesized taking into account the primary structure of Cry11Bb endotoxin, is active against several species of bacteria. In this work we show that BTM-P1 induces cyclosporin A-insensitive swelling of rat liver mitochondria in various salt solutions but not in the sucrose medium. Inorganic phosphate and Ca2+significantly increased this effect of the peptide. The uncoupling action of BTM-P1 on oxidative phosphorylation was stronger in the potassium-containing media and correlated with a decrease of the inner membrane potential of mitochondria. In isotonic KNO3, KCl, or NH4NO3media, a complete drop of the inner membrane potential was observed at 1–2 μg/ml of the peptide. The peptide-induced swelling was increased by energization of mitochondria in the potassium-containing media, but it was inhibited in the NaNO3, NH4NO3, and Tris-NO3media. All mitochondrial effects of the peptide were completely prevented by adding a single N-terminal tryptophan residue to the peptide sequence. We suggest a mechanism of membrane permeabilization that includes a transmembrane- and surface potential-dependent insertion of the polycation peptide into the lipid bilayer and its oligomerization leading to formation of ion channels and also to the mitochondrial permeability transition pore opening in a cyclosporin A-insensitive manner.

scholarly journals Selective inhibition of CYP27A1 and of chenodeoxycholic acid synthesis in cholestatic hamster liver

2002 ◽  
Vol 1588 (2) ◽  
pp. 139-148 ◽  
Author(s):  
Yasushi Matsuzaki ◽  
Bernard Bouscarel ◽  
Tadashi Ikegami ◽  
Akira Honda ◽  
Mikio Doy ◽  
...  
Keyword(s):  
Chenodeoxycholic Acid ◽  
Selective Inhibition ◽  
Acid Synthesis
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