Liver cell death in alcoholic liver disease occurs predominantly in the centrilobular (periacinar) areas of the liver that (a) are exposed to low oxygen tensions and (b) are most active in transforming some substances into toxic electrophiles. Glutathione (GSH), known to protect against these toxic substances, is lowest in the centrilobular zone. Acute ethanol administration leads to marked increases in liver oxygen consumption and in splanchnic blood flow. These effects can be produced by the administration of glucagon. It is hypothesized that the effects of ethanol on splanchnic oxygen consumption and on splanchnic blood flow are mediated by glucagon, the levels of which are markedly increased by acute ethanol administration. Since glucagon is released into the portal blood and is largely cleared by the liver, moderate increases in glucagon, at low levels of ethanol, are expected to result in increases in liver oxygen consumption that are not accompanied by increases in splanchnic blood flow. Studies will be conducted to test this hypothesis. Acute ethanol administration markedly reduces liver GSH levels, an effect that is also shared by glucagon. The mechanism(s) of liver GSH depletion induced by ethanol, and the centrilobular or periportal localization of this effect will be investigated. The compensatory mechanisms for liver GSH repletion following chronic alcohol administration will also be studied. In human alcoholics who develop alcoholic liver disease the compensatory mechanisms for GSH repletion would appear to be deficient. We postulate that chronic alcohol treatment induces mechanisms that lead to an increased availability of GSH precursors to the liver. One such mechanism is the transformation of methionine into cysteine and a second one is the operation of gamma glutamyl transferase as a compensatory mechanism to recover GSH precursors from extracellular GSH. Hepatic gamma glutamyl transferase is markedly and consistently increased by chronic ethanol consumption but the significance of such increase is not known. The studies investigate the physiological role of this enzyme in the transport of aminoacids in the liver of animals fed alcohol chronically as well as in controls.
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