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The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatidylinositol (PtdIns) phosphatase that regulates Akt activation via PtdIns 3 kinase. Changes in PTEN expression and/or activity have been identified in a variety of chronic hepatocellular disorders including obesity, NAFLD, NASH, and alcoholism. In cancer biology, PTEN is frequently mutated or deleted in a wide variety of tumors. Mutations, decreased promoter activity, and decreased expression in PTEN are frequently identified in patients with hepatocellular carcinoma. While the majority of research on PTEN concerns obesity and NASH, PTEN clearly has a role in hepatic insulin sensitivity and in the development of steatosis during chronic alcoholism. Yet, in chronic alcoholics and HCC, very little is known concerning PTEN mutation/deletion or low PTEN expression. This review is focused on an overview of the current knowledge on molecular mechanisms of dysregulation of PTEN expression/activity in the liver and their relationship to development of ethanol-induced hepatocellular damage and cancer.

Long-sleep (LS) and Short-sleep (SS) male mice were treated chronically with alcohol for 30 days. Ethanol treated mice were withdrawn from alcohol diet at 8, 12, 16, 20, 24 and 30 days of treatment for the assessment of metabolic tolerance and numerous parameters associated with the microsomal cytochrome P-450 complex. Up to 20 days of ethanol treatment, LS and SS mice displayed nearly the same enhancement of in vivo ethanol elimination rates. AT 24 and 30 days of ethanol treatment, LS mice were found to have significantly greater ethanol elimination rates than SS mice chronically treated with alcohol. The induction of microsomal cytochrome P-450 content and microsomal ethanol oxidation paralleled the acquisition of metabolic tolerance with LS mice displaying significantly greater values of both microsomal parameters at 24 and 30 days of treatment. Aniline hydroxylase was maximally induced (2.5 fold) in both LS and SS mice by 16 days of treatment. Chronic ethanol treatment resulted in a significant induction of ethylmorphine and benzphetamine N-demethylase activity in both LS and SS mice with the SS selected line showing a greater (P < .05) maximal induction. These data are suggestive that the induction of MEOS may have some significance in the acquisition of metabolic tolerance to ethanol and that there may be a genetic predisposition for these adaptive responses.

Cytosolic aldehyde dehydrogenase (AlDH) activity was increased in DBA and C57Bl mice following phenobarbital (Pb) treatment. The kinetic constants for the control and induced enzymes were similar in both inbred strains. The DBA mice showed enhanced rates of ethanol and acetaldehyde metabolism after Pb treatment, whereas the C57Bl mice did not. It was concluded that the cytosolic enzyme is more important for acetaldehyde metabolism in the DBA than in the C57Bl mice.