Reduced hepatic content of dehydroepiandrosterone sulphotransferase in chronic liver diseases

Elekima, Obadiah T. Lulu; Mills, Charles O.; Ahmad, Afshan; Skinner, G. R. B.; Ramsden, D.; Bown, Jonathan A.; Young, Tom; Elias, Elwyn

doi:10.1034/j.1600-0676.2000.020001045.x

Cited by 26 publications

(20 citation statements)

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“…To understand the contribution of these enzymes to the xenobiotic and endobiotic metabolism, we must elucidate the enzymes' characteristics, including their tissue expression, activity, and regulation. Human sulfotransferases have been well characterized in healthy liver tissues (Riches et al, 2009), but little has been reported in diseased liver tissue (Elekima et al, 2000;Yeo et al, 2010;Hardwick et al, 2013). In this paper, we report sulfotransferase activity and expression in healthy liver tissue versus tissue of individuals diagnosed with steatosis, diabetes, diabetic cirrhosis, and alcohol cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

Yalçın

Neira

et al. 2013

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 99%

Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

Yalçın

Neira

et al. 2013

Drug Metab Dispos

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“…STA2 encodes a cytosolic hydroxysteroid-specific sulfotransferase, which is involved in limiting the amount of active androgens in cells (12) and also in detoxification of cholestatic hydroxylated bile acids, such as lithocholic acid (23,36). In humans, low levels of hydroxysteroid sulfotransferase activity were shown to correlate with chronic liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, chronic active hepatitis, and alcoholic cirrhosis (17). Thus, STA2 may be important for detoxification of bile acids originally derived from cholesterol, which is released in excess from malaria-destroyed erythrocytes during the crisis of infections.…”

Section: Discussionmentioning

confidence: 99%

Testosterone Suppresses Protective Responses of the Liver to Blood-Stage Malaria

et al. 2005

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Testosterone induces a lethal outcome in otherwise self-healing blood-stage malaria caused by Plasmodium chabaudi. Here, we examine possible testosterone effects on the antimalaria effectors spleen and liver in female C57BL/6 mice. Self-healing malaria activates gating mechanisms in the spleen and liver that lead to a dramatic reduction in trapping activity, as measured by quantifying the uptake of 3-m-diameter fluorescent polystyrol particles. However, testosterone delays malaria-induced closing of the liver, but not the spleen. Coincidently, testosterone causes an ϳ3-to 28-fold depression of the mRNA levels of nine malaria-responsive genes, out of 299 genes tested, only in the liver and not in the spleen, as shown by cDNA arrays and Northern blotting. Among these are the genes encoding plasminogen activator inhibitor (PAI1) and hydroxysteroid sulfotransferase (STA2). STA2, which detoxifies bile acids, is suppressed 10-fold by malaria and an additional 28-fold by testosterone, suggesting a severe perturbation of bile acid metabolism. PAI1 is protective against malaria, since disruption of the PAI1 gene results in partial loss of the ability to control the course of P. chabaudi infections. Collectively, our data indicate that the liver rather than the spleen is a major target organ for testosteronemediated suppression of resistance against blood-stage malaria.

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“…6 When later it became clear that lithocholic acid sulphotransferase activity resided in dehydroepiandrosterone sulphtransferase (DHEAST) (still later isoform SULT2A1) we demonstrated reduced activity in end-stage liver tissue from primary biliary cirrhosis, primary sclerosing cholangitis and other selected liver diseases. 7 These studies were not able to distinguish diminished enzyme activity that was primary and potentially causal from diminished function that arose as a consequence of the disease within the liver. We therefore performed a series of in vitro experiments utilising the hepatocyte couplet model (Fig 4) in the laboratories of the late Professor Roger Coleman.…”

Section: Defective Mechanisms and Disease Susceptibilitymentioning

confidence: 99%

Coordinated defence and the liver

Elias

Mills

2007

Clinical Medicine

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-The liver is strategically placed to protect the body against a vast array of potentially harmful compounds. The steps involved include phase I metabolism which makes molecules more reactive and phase II reactions which generally enhance solubility in bile or urine. Recent discoveries have shown how regulation of these reactions is also closely allied to expression of membrane transporters which excrete the products of biotransformation into bile and prevent their reabsorptoion via the intestine. The coordinated activity of these various functions is orchestrated by orphan nuclear receptors which, in response to an encounter with a potential toxin, are able to induce expression of the genes involved in its biotransformation and excretion. Lithocholic acid (LCA) is routinely produced in our intestine by bacterial deconjugation of chenodeoxycholic acid a major bile acid in humans. In human liver the presence of LCA is sensed by the pregnane X receptor (PXR) which has the potential to switch on all the genes required for safe metabolism and elimination of LCA from the body. These include cytochrome P450 3A which hydroxylates LCA to more soluble forms and sulfotransferase (SULT2A1) which by sulphation of LCA makes it more readily soluble in bile and enhances its faecal excretion. Similarly, PXR exposure to LCA produces up-regulated expression of the membrane transporters MDR1 and MRP2 which excrete metabolites of LCA. Evidence is accumulating in support of the hypothesis that deficiencies in these defence mechanisms underlie susceptibility to primary sclerosing cholangitis and ulcerative colitis. KEY WORDS: cytochrome P450 3A, lithocholic acid, MDR1 and MRP2, orphan nuclear receptors, pregnane X receptor, sulphation, susceptibility to primary sclerosing cholangitis, ulcerative colitisThe liver metabolises and excretes a host of endogenous molecules and stands at the portal of entry for all kinds of ingested xenobiotics, whether food or drug. The fate of these compounds depends largely on the efficiency of their absorption from the gut and uptake and biotransformation by the liver. The mechanisms involved include metabolic transformation and active transport which usually work in combination to enhance elimination from the body whether in urine or faeces. In this the liver is closely allied with the intestine in maintaining the functionality of bile as a safe route for elimination of any potentially toxic compound that lacks sufficient solubility in water to permit its efficient excretion via the kidneys. The detergent properties of bile facilitate efficient excretion of compounds which are poorly soluble in water. Coordinated biliary defence mechanismsBile acids provide the required detergency and are essential for biliary cholesterol secretion and absorption of fat and fat soluble vitamins. The synthesis of bile acids by the liver is closely regulated to compensate for faecal loss, thus maintaining a consistent pool of bile acids in the entero-hepatic circulation which re-circulate from liver to intestine...

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Reduced hepatic content of dehydroepiandrosterone sulphotransferase in chronic liver diseases

Abstract: These results confirm that DHEA ST activity is diminished in liver disease and that the reduction is due to diminished enzyme presence. Further studies are required to show whether the reduction has any pathogenetic significance or is merely a consequence of disease.

Cited by 26 publications

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Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

Testosterone Suppresses Protective Responses of the Liver to Blood-Stage Malaria

Coordinated defence and the liver

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