Liver toxicity adaptive responses

Cholestasis is a condition characterized by impaired flow of bile, due to physical obstruction of the biliary tree or decreased bile secretion by the liver. Cholestasis produces alterations of enzyme activity in the liver (cytochrome P450) as well as altered transporter expression, with associated effects on drug clearance. As discussed previously, cholestasis can occur through inhibition of the canalicular membrane transporter, BSEP. In response to cholestasis, however, the liver has adaptive mechanisms to minimize cellular accumulation of toxic bile salts. These include upregulation of MRP3 to increase sinusoidal efflux, and downregulation of Na -taurocholate cotransporting polypeptide (NTCP), which mediates bile salt uptake from the blood to the liver. 

Our questions broadened to consider how the transport and metabolic capabilities of these aquatic species compare with those of mammalian species. One reason for asking such a question is to assess whether the presence or absence of these capabilities alters the ability of fish to survive in toxic environments. Survival mechanisms fall into two catagories - behavioral and physiologic. An example of a behavioral mechanism could be as simple as a fish avoiding that area of a stream which contains toxic quantitites of phenol. When external perturbations caused by pollutants are small, homeostatic mechanisms such as those of the liver and kidney, allow fish to adapt to the body of water in which they exist. The problem then is related to defining the limits to which homeostatic phenomena can be stressed in aquatic species. An important reason to establish such information in fish is that bodies of water are the "ultimate sink" for a number of pollutants (12). Thus, while a behavioral response such as removing itself from a toxic environment is invariably available to a mammalian species, this type of response is impossible for a fish if a toxic xenobiotic occurs uniformly throughout an entire body of water. 

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