Human class I alcohol dehydrogenase (ADH) is encoded by three genes (ADH1, ADH2, and ADH3) which display differential patterns of tissue-specific and developmental gene expression. ADH catalyzes the oxidation of a wide variety of xenobiotic or endogenous alcohols. In addition to the rate-limiting step in ethanol metabolism, ADH catalyzes vitamin A (retinol) oxidation which is the rate-limiting step in the conversion of retinol to retinoic acid, a hormone known to control gene expression at the transcriptional level. Retinoic acid is necessary for morphogenesis of several-embryonic tissues (such as hindbrain and limb buds) and maintenance of the differentiated state of adult epithelial tissues. Human ADH is expressed primarily in the liver, but also in other epithelial cells such as intestine, kidney and lung. ADH may exist in many epithelial cells to catalyze retinoic acid synthesis, and the large amount of ADH in the liver may relate to the fact that this is the site of retinol storage and turnover (degradation). Analysis of the regulation of ADH gene expression is beginning to clarify the importance of ADH in liver development and retinoic acid-regulated processes. We have determined that ADH2 transcription is controlled by a liver transcription factor called C/EBP which helps establish high level transcription in the liver. In addition, we have determined that ADH3 transcription is regulated by retinoic acid. We have hypothesized that this constitutes a positive feedback loop for establishing retinoic acid synthesis since ADH catalyzes the rate-limiting step in retinoic acid synthesis. We have further hypothesized that this retinoic acid homeostatic mechanism may be overcome by excess ethanol, leading to fetal alcohol syndrome characterized by defects in embryonic brain and limb tissues requiring critical levels of retinoic acid for proper development. Fetal alcohol syndrome is the single most prevalent cause of mental retardation, leading to recommendations that pregnant women abstain from alcohol use. Since we do not know how ethanol damage occurs, further studies on the mechanism are needed. To further analyze the role ADH plays in retinoic acid homeostasis we intend to perform studies which address the generality of ADH gene regulation by retinoic acid in humans and other mammals, as well as further studies on the mechanism of ADH gene expression. The goals for this proposal are as follows: (1) Analyze retinoic acid induction of ADH genes in mouse cell lines and embryos in order to identify the mouse homolog of the retinoic acid-inducible human ADH3 gene; (2) Clone additional mouse ADH genes including a retinoic acid-inducible form; (3) Further analyze the retinoic acid response element in the human ADH3 gene using transfection studies; (4) Produce transgenic mice carrying the human ADH3 promoter fused to the easily assayable lacZ gene to study ADH3 regulation in vivo; (5) Analyze the ADH1, ADH2, and ADH3 genes for regulation by several known liver transcription factors to discover the nature, of the transcriptional events leading to high level transcription in the liver and low levels elsewhere.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Biochemistry, Physiology and Medicine Subcommittee (ALCB)
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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Mic, Felix A; Haselbeck, Robert J; Cuenca, Arnold E et al. (2002) Novel retinoic acid generating activities in the neural tube and heart identified by conditional rescue of Raldh2 null mutant mice. Development 129:2271-82
Duester, G (2001) Genetic dissection of retinoid dehydrogenases. Chem Biol Interact 130-132:469-80
Hoffmann, I; Ang, H L; Duester, G (1998) Alcohol dehydrogenases in Xenopus development: conserved expression of ADH1 and ADH4 in epithelial retinoid target tissues. Dev Dyn 213:261-70
Haselbeck, R J; Duester, G (1998) ADH1 and ADH4 alcohol/retinol dehydrogenases in the developing adrenal blastema provide evidence for embryonic retinoid endocrine function. Dev Dyn 213:114-20
Haselbeck, R J; Duester, G (1998) ADH4-lacZ transgenic mouse reveals alcohol dehydrogenase localization in embryonic midbrain/hindbrain, otic vesicles, and mesencephalic, trigeminal, facial, and olfactory neural crest. Alcohol Clin Exp Res 22:1607-13
Duester, G; Deltour, L; Ang, H L (1997) Evidence that class IV alcohol dehydrogenase may function in embryonic retinoic acid synthesis. Adv Exp Med Biol 414:357-64
Haselbeck, R J; Ang, H L; Duester, G (1997) Class IV alcohol/retinol dehydrogenase localization in epidermal basal layer: potential site of retinoic acid synthesis during skin development. Dev Dyn 208:447-53
Ang, H L; Duester, G (1997) Initiation of retinoid signaling in primitive streak mouse embryos: spatiotemporal expression patterns of receptors and metabolic enzymes for ligand synthesis. Dev Dyn 208:536-43
Duester, G (1994) Retinoids and the alcohol dehydrogenase gene family. EXS 71:279-90
Zgombic-Knight, M; Satre, M A; Duester, G (1994) Differential activity of the promoter for the human alcohol dehydrogenase (retinol dehydrogenase) gene ADH3 in neural tube of transgenic mouse embryos. J Biol Chem 269:6790-5

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