Coordinated defence and the liver

Abstract

-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...

Alteration of amino acid and biogenic amine metabolism in hepatobiliary cancers: Findings from a prospective cohort study

“…23,24 Altered AA profiles may also result from liver defence processes, such as activation of specific defence proteins and production of AA derivatives, which are triggered in order to protect liver cells from injury. [25][26][27] In this study, several identified associations support these assumptions.…”

“…For example in the case of hepatocellular damage, the brain, kidney or skeletal muscles may take over some metabolic processes that cannot be fully supported by the impaired liver . Altered AA profiles may also result from liver defence processes, such as activation of specific defence proteins and production of AA derivatives, which are triggered in order to protect liver cells from injury . In this study, several identified associations support these assumptions.…”

“…Some of our observations may also be reflective of protective functions of certain metabolic pathways which are activated in order to protect liver cells from injury . An inverse HCC risk association was observed for glutamine.…”

Effects of fluoroquinolone treatment on MDR1 and MRP2 mRNA expression inEscherichia coli-infected chickens

“…*PB0.05 compared with uninfected controls. (Elias & Mills, 2007). Several diseases, including obstructive cholestasis, are associated with a down-regulation of hepatic ABC transporters during the acute phase response to infection (Geier et al, 2007).…”

Regulation of hepatic ABCC transporters by xenobiotics and in disease states

“…Human liver MRP2 expression is upregulated by exposure to lithocholic acid (Elias and Mills, 2007). In healthy gallstone patients, treatment with ursodeoxycholic acid (1 g/day for 3 weeks) does not change significantly MRP2 mRNA or protein expression (Marschall et al, 2005).…”