mariadistel tijdens anavar

[Cools]

Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: A 30-month pilot study
[Link niet meer beschikbaar]

Regulation of bile acid synthesis in humans: Effect of treatment with bile acids, cholestyramine or simvastatin on cholesterol 7α-hydroxylation rates in vivo
http://onlinelibrary.wiley.com/doi/10.1002/hep.1840140515/abstract

Ursodeoxycholate reduces hepatotoxicity of bile salts in primary human hepatocytes
http://onlinelibrary.wiley.com/doi/10.1002/hep.1840120307/abstract

Oat bran stimulates bile acid synthesis within 8 h as measured by 7α-hydroxy-4-cholesten-3-one
http://www.ajcn.org/content/76/5/1111.short


Serum 7 alpha-hydroxy-4-cholesten-3-one concentrations in the evaluation of bile acid malabsorption in patients with diarrhoea: correlation to SeHCAT test.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1374193/

The synthesis of bile acids is regulated by a homeostatic mechanism in which bile acids returning to the liver from the intestine inhibit their own synthesis.


Effect of long term simvastatin administration as an adjunct to ursodeoxycholic acid: evidence for a synergistic effect on biliary bile acid composition but not on serum lipids in humans
http://gut.bmj.com/content/44/4/552.abstract


Stimulated bile acid synthesis preferentially utilises newly synthesised cholesterol, raising the posssiblity that combination of simvastatin (an inhibitor of cholesterol synthesis) with ursodeoxycholic acid (UDCA; a stimulator of bile acid synthesis) may result in reduced bile acid synthesis and greater enrichment of the pool with UDCA than that achieved with UDCA treatment alone


Role of FXR in regulating bile acid homeostasis and relevance for human diseases.
http://www.ncbi.nlm.nih.gov/pubmed/16178789

Because of their intrinsic toxicity, bile acid synthesis, transport, and metabolism must be tightly regulated. It is now apparent that members of the nuclear receptor family of lipid-activated transcription factors are key regulators of these physiological processes.



I. Nuclear receptors and bile acid homeostasis
http://ajpgi.physiology.org/content/282/6/G926.short

Recent studies reveal that bile acids are signalling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis.
In vivo administration of 6-ECDCA protects against cholestasis induced by estrogen and LCA in rats providing evidence that development of potent FXR agonists might represent a new approach for the treatment of cholestastic disorders.


The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity
http://www.pnas.org/content/98/6/3369.short

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16α-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals.
Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7α-hydroxylase (Cyp7a1) and the Na+-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.


Nuclear receptors in liver disease †
http://onlinelibrary.wiley.com/doi/10.1002/hep.24148/abstract

Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of hepatic physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes including hepatic lipid metabolism, drug disposition, bile acid homeostasis, as well as liver regeneration, inflammation, fibrosis, cell differentiation, and tumor formation. Derangements of nuclear receptor regulation and genetic variants may contribute to the pathogenesis and progression of liver diseases. This places nuclear receptors into the frontline for novel therapeutic approaches for a broad range of hepatic disorders and diseases including cholestatic and fatty liver disease, drug hepatotoxicity, viral hepatitis, liver fibrosis, and cancer.


Effects of Endogenous Steroids on CYP3A4-Mediated Drug Metabolism by Human Liver Microsomes
http://dmd.aspetjournals.org/content/30/5/534.short

These data demonstrate that endogenous steroids, especially androgens, strongly affect CYP3A4-mediated drug metabolism in vitro. The postulated mechanisms of the interactions between AND and CBZ or ZNS are discussed.


Selective activation of liver X receptor alpha by 6alpha-hydroxy bile acids and analogs.
http://www.ncbi.nlm.nih.gov/pubmed/10936612

Enzymes in the Conversion of Cholesterol into Bile Acids
http://www.ingentaconnect.com/content/ben/cmm/2007/00000007/00000002/art00005

Inhibition of ileal bile acid transport lowers plasma cholesterol levels by inactivating hepatic farnesoid X receptor and stimulating cholesterol 7 alpha-hydroxylase.
http://www.ncbi.nlm.nih.gov/pubmed/15254889

 

[Cools]

CHOLESTASIS
Ther term cholestasis refers to the suppression of bile secretion. Biliary constituents
may therefore be retained within the hepatocyte and regurgitated into the systemic
circulation. Cholestasis causes three major groups of negative effects: first,
regurgitation of bile components (bile acids, bilirubin) into the systemic circulation
gives rise to the symptoms of jaundice and pruritus (itching). Second, cholestasis
damages hepatocytes, as evidenced by the release of "liver enzymes" (e.g., alkaline
phosphatase) into the plasma. Third, because the bile acids do not arrive in the
duodenum, lipid digestion and absorption may be impaired.
Many acute and chronic liver diseases produce cholestasis by mechanically
obstructing the extrahepatic bile ducts or impairing bile flow at the level of the
hepatocytes or intrahepatic bile ducts. The mechanisms underlying the obstructive
and functional forms of cholestasis are complex and have not been completely
defined. Experimental models of cholestasis have produced multiple abnormalities:
(1) altered plasma membrane composition and fluidity; (2) inhibition of membrane
proteins, including the Na-K pump; (3) reduced expression of genes encoding
transporters for bile acids and other organic anions; (4) increased permeability of
the paracellular pathway, with backdiffusion of biliary solutes into the plasma; (5)
altered function of microfilaments, with decreased contractions of bile canaliculi;
and (6) loss of the polarized distribution of some plasma membrane proteins

 

[Cools]

Bovenstaande onderzoeken leggen uit hoe de galzuuraanmaak en transport gereguleerd wordt. De positieve en protectieve effecten van ursodeoxycholzuur worden ook aangegeven.

De effecten van aas op deze dingen worden in de volgende onderzoeken uitgelegd. Ook de effecten van mariadistel volgen. (zal voor deze avond zijn)

 

[Cools]

Effect of Silybin and its congeners on human liver microsomal cytochrome P450 activitie
http://onlinelibrary.wiley.com/doi/10.1002/ptr.1000/abstract

The inhibition was competitive or mixed as revealed by double reciprocal plots of kinetic experiments. However, the inhibition is not considered to be relevant for therapy because physiological concentrations of the individual flavonolignans do not exceed 0.5 μM. The data support the use of the extract as a dietary supplement.

Inhibitory Effects of Silibinin on Cytochrome P-450 Enzymes in Human Liver Microsomes
http://onlinelibrary.wiley.com/doi/10.1111/j.0901-9928.2000.860602.x/abstract

Inhibition was competitive for S(−)-warfarin 7-hydroxylation (Ki,c=18 μM and 19 μM) and mainly non-competitive for denitronifedipine oxidation (Ki,n=9 μM and 12 μM). With therapeutic silibinin peak plasma concentrations of 0.6 μM and biliary concentrations up to 200 μM, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded.


Primary cultures of human hepatocytes as a tool in cytotoxicity studies: cell protection against model toxins by flavonolignans obtained from Silybummarianum
http://www.sciencedirect.com/science/article/pii/S037842740200406X

 

[SIA]

Zeer interessante onderzoeken. Ik zal zeker het een en ander onder mijn favorieten zetten.
Maar laten we niet afdwalen en on-topic blijven want anders wordt het wel erg beknopt allemaal.

Heb even snel in je laatste 3 bijdragen gekeken en ja, het zegt eigenlijk helemaal niets.
De middelste heb ik zelf al gepost.
Eerste twee geeft enkel maar een daling van enzymen uit de P450 stam aan, niets meer.
De laatste is niet relevant aangezien het niet relateert met cholestase.
Kijk ook even naar de middelen die zijn gebruikt.

 

[Cools]

Bij interhepatische cholestase moet je de galzuurpomp en transporters activeren. Deze soort cholestase wordt ook veroorzaakt door inhibitie ervan.

Nu heeft mariadistel niet alleen effect op de productie maar ook toevoer en afvoer (in de dunne darm) van galzuren. Dus bij interhepatische cholestase is mariadistel een noodzaak. Anders zullen de galzuren zich opbouwen in de cellen en toxiciteit veroorzaken.

Als er volledig geen galproductie meer is door beschadiging van bepaalde cellen gaat mariadistel niet werken, net zoals bij cholestase door ontsteking (blokkering) van de galwegen.

De middelste heb ik terug gepost ter vergelijking. Het geeft aan dat inhibitie door de inviduele stoffen in mariadistel niet relavant zijn omdat de fysiologische concentraties niet hoog genoeg komen. De laatste geeft bepaalde protectieve eigenschappen al aan.

However, the inhibition is not considered to be relevant for therapy because physiological concentrations of the individual flavonolignans do not exceed 0.5 μM.

Alle bovenstaande onderzoeken hebben te maken met de aanmaak, werking en transport van galzuren. Nu hebben alle hormonen effect op de werking van cyp enzymen. Het zijn inhibitors en/of substraten van specifieke enzymen. De invloed op die enzymen heeft een positieve of negatieve feedback op de aanmaak en transport van galzuren. Galzuren worden alleen toxisch als ze nergens heen kunnen.


Ook interessant deze.

Phase I and II Detox Pathways
[Link niet meer beschikbaar]

Xenobiotic metabolism
http://en.wikipedia.org/wiki/Xenobiotic_metabolism

Mariadistel zou fase 1 versnellen en fase 2 vertragen. Ik ga deze avond nog eens wat verder in de onderzoeken graven hierover. Ik was al een tijdje van plan hier een apart topic over te maken, maar is er niet van gekomen door tijdsgebrek.