The present investigation will focus on the effects of alcohol on the liver and employs both in vitro and in vivo model systems. One of the major biologic effects of alcohol is the capacity to inhibit liver repair following cellular injury. Therefore, we will explore the action of ethanol on hormone stimulated hepatocyte DNA synthesis and perform detailed studies on the mechanisms of the ethanol effect using primary hepatocyte cultures. These investigations will examine the effects of ethanol on the binding of epidermal growth factor (EGF) and insulin to liver cell membranes and to observe whether ethanol modifies the action of these hormones by studying receptor binding, polyamine biosynthesis and metabolism, and phosphorylation of tyrosine and serine residues. We also plan to examine the usefulness of nuclear magnetic resonance (NMR) to study liver injury steatosis following in vivo ethanol administration. Such investigations employ NMR spectroscopy and imaging, NMR chemical shift imaging and potential use of paramagnetic probes designed to enhance spin-lattice relaxation times (T1 and T2). For example, we are developing paramagentic agents such as Gd+++ covalently linked to asialoglycoproteins in an attempt to enhance or change NMR contrast within the liver; these studies will hopefully provide in vivo diagnostic information on liver injury and steatosis. Finally, we believe that the capacity of ethanol to inhibit hepatocyte DNA synthesis may have biologic relevance to why patients with severe alcohol induced liver injury fail to recover despite cessation of alcohol intake. The use of emerging NMR technology will further permit us to explore the hepatic changes produced by ethanol and may allow for the early identification of alcohol induced liver injury and steatosis in man.
