REGULATION OF EXPRESSION OF LIVER ALCOHOL DEHYDROGENASE

Project: Research project

Description

The major determinants of the pharmacological, addictive, and pathological
effects of alcohol consumption are the tissue concentrations of ethanol and
its metabolic products, and the duration of exposure to these compounds.
There are significant variations in individual alcohol elimination rates
among human subjects. The activity of liver alcohol dehydrogenase (ADH) is
an important determinant of alcohol elimination rate and may be controlled
by the kinetic properties of ADH isoenzymes and by the total liver content
of ADH. The rat is a useful animal model for studies on the regulation of
liver ADH content because it exhibits only two major molecular forms of ADH
and the total enzyme activity is under genetic, developmental and endocrine
control. In order to understand the mechanisms of regulation of liver ADH
activity in rats, the following studies will be performed: 1) The two
purified molecular forms of liver ADH will be characterized by peptide
mapping and kinetic analysis. These studies are necessary to interpret
later experiments involving measurement of levels ADH mRNA. 2) The
differences in liver ADH activity between Sprague-Dawley and ACI/N rates
will be examined by a) determining the molecular properties and peptide
maps of purified enzyme from each strain, b) evaluating the mode of
inheritance of this trait by classical genetic crosses of F1 offspring and
parental strains and c) measuring the turnover of ADH and levels of ADH
mRNA in the two strains to determine whether the difference in activity is
due to differences in rates of synthesis or degradation. 3) The role of
thyroid hormone in the developmental control of ADH activity will be
assessed by evaluating the effect of propylthiouracil-induced
hypothyroidism in neonatal rats and by measuring ADH turnover and mRNA
levels in thyroidectomized animals. 4) The newly discovered role of the
pituitary in the sexually differentiated expression of ADH will be examined
by a) chronically infusing growth hormone into male and female rats, b)
determining the effect on ADH activity of electrolytic lesions of the
hypothalamus which are known to increase growth hormone secretion and c)
evaluating the effect of neonatal androgen exposure which is known to
influence subsequent patterns of pituitary hormone secretion in adult
animals. 5) To establish a simpler system for the study of hormonal
control of liver ADH activity, primary hepatocyte cultures will be used to
determine the medium, serum, and hormone requirements for normal rates of
ADH synthesis.
StatusFinished
Effective start/end date5/1/858/31/05

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $318,646.00
  • National Institutes of Health: $330,120.00
  • National Institutes of Health: $291,485.00
  • National Institutes of Health
  • National Institutes of Health: $372,868.00
  • National Institutes of Health
  • National Institutes of Health: $150,332.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $394,500.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $194,876.00
  • National Institutes of Health
  • National Institutes of Health: $402,534.00
  • National Institutes of Health: $380,252.00
  • National Institutes of Health
  • National Institutes of Health

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Alcohol Dehydrogenase
Aldehyde Dehydrogenase
Alcoholism
Mutation
Liver
Aptitude
Retinoids
Ethanol
RNA Stability
Genes
Hormones
Transfection
Messenger RNA
Kidney
Enzymes
Ligands
Gene Expression
PPAR alpha
Exons
Peroxisome Proliferator-Activated Receptors

ASJC

  • Medicine(all)