The objectives of the proposal are: 1) To investigate the mechanisms by which growth hormone (GH) regulates the expression of the rat class I alcohol dehydrogenase (ADH) gene and 2) To study the effects of ethanol on the ADP ribosylation of hepatocyte nuclear proteins as it relates to the effects of ethanol and/or acetaldehyde on DNA damage, DNA synthesis and gene expression. Proteins from rat liver nuclear extracts bound to 3 regions of the rat ADH promoter, designated as 1, 2, and 3 corresponding to positions -2 to -18, -36 to -44 and -52 to -60 relative to the start-site of transcription. CCAAT/enhancer binding protein (C/EBP) is one of the nuclear proteins that binds to region 1, and additional factors that interact with this site will be investigated. Region 2 has the binding sequence for a protein that functions cooperatively with the glucocorticoid receptor and will not be studied further. Region 3 appears to interact with the protein upstream regulatory factor and this interaction will be characterized further. The cis-acting element(s) within the ADH promoter that are required for GH to act will be determined by transfection experiments in both primary heptocyte culture and HepG2 cells using ADH promoter constructs. Lastly, the effect of GH on candidate protein(s) responsible for regulating expression of the ADH gene will be examined directly. Studies in the second objective of the proposal will determine the time course and reversibility of ethanol-induced enhancement of poly (ADP-ribose) polymerase activity and ADP-ribosylation of proteins in hepatocyte culture, and the role of these changes in the inhibitory effect of ethanol on DNA synthesis. Study of mechanisms for the ethanol-induced increase in poly (ADP-ribose) polymerase will concentrate on whether it is a consequence of ethanol or acetaldehyde induced mutagenicity as evidenced by sister-chromatid exchanges or DNA strand breaks or results from activation of poly (ADP-ribose) glycohydrolase which removes poly (ADP- ribose) residues from poly (ADP-ribose) polymerase reversing inhibition caused by autoribosylation. Histone and non-histone proteins whose ribosylation is augmented by ethanol will be identified. The binding of histone H1 to the alpha2(I) collagen promoter and the effect of its ribosylation on the binding to and expression of this collagen gene will be studied.
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