Canalicular membrane permeability

Cholestatic jaundice has often been reported with oral estrogens and is probably related to an effect on the permeability of the canalicular membrane (SEDA-20, 381). Cholestatic jaundice induced by a subcutaneous estrogen implant has also been reported in the absence of any other cause of liver disease (SEDA-20, 381). After... 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

PS3 Permeability surface area product for the excretion across the canalicular membrane... 

Because the compound accesses this compartment by crossing both the plasma membrane and the canalicular membrane, it also has to be membrane permeable, requiring a log P of between -3 and 0. Too high a log P drives the chemical into the hydrophobic domain of the membrane bilayer, perhaps decreasing access to the target or generating an inappropriate target site too low a log P reduces membrane permeability and access to the acid space. 

The bile canalicular membrane, which is oriented opposite the sinusoid, comprises approximately 13% of the hepatocyte surface. In drug-induced cholestasis, the cytoskeleton (microfilament network) of the canalicular membrane undergoes changes in membrane fluidity (permeability). There is loss of tone, pulsatile function, or both. 

The nature and origin of the permeability which is associated with the H,K ATPase in the canaliculus remain undefined. It has been proposed that the canalicular membrane contains parallel conductances for and CT or alternatively that there is a KCl cotransporter. Further, the proteins that interact with the enzyme in the cytoplasmic membranes that enable stimulus-dependent conversion to the canalicular form remain elusive, although ezrin and actin are clearly associated with the enzyme in its stimulated form. 

Activity of the H,K ATPase results In a primary secretion of 160 mM of HCl Into the secretory canaliculus. Because the H,K ATPase Is electroneutral. It Is necessary that the KCl permeability pathway assodated with the canaliculus transfer a minimum of 160 mmol of KCl for each liter of acidic fluid secreted. This Is true whether the KCl pathway consists of conductive or electroneutral transporters. It Is likely. In fact, that the KCl pathway allows transfer of a slight excess of KCl over the minimum required for the production of HCl. This Is suggested both by the observation that gastric secretions contain a low but significant concentration of KCl and by the likelihood that the H,K ATPase Is not fully efficient at recovering K from the canalicular fluid. In the absence of other mechanisms, the combined activity of the transporters at the apical pole of the parietal cell would lead to alkallnizatlon of the cell and depletion of cellular Cl" and K. The potential disturbances In electrolyte balance are prevented by the activity of transporters at the basolateral membrane. These Include an anion exchanger (AE, HCOj /Cl"), a sodlum/proton exchanger (NHE), and the Na,K ATPase. 

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