The effects of chronic alcohol consumption and of alcohol, in vitro, on the structure and function of mitochondrial membranes from liver, brain and the erythrocyte plasma membrane, will be investigated. Studies with mitochondria from rat liver and brain will focus on the mechanism of the alcohol-induced reduction in the efficiency of oxidative phosphorylation. In addition to conventional assays of enzyme activity, 31P-NMR, phosphorescence anisotropy, fluorescence energy transfer and other biophysical techniques will be utilized in these studies. The effect of alcohol on the metabolism of amino-acid neurotransmitters in brain mitochondria will also be investigated. The partition of ethanol, anesthetics and cholesterol into various membranes will be studied in great detail, using radioactive, fluorescence quenching and NMR techniques. These studies should lead to a better understanding of the mechanisms by which the reduced partition of ethanol, which is postulated to lead to membrane resistance (tolerance), is acquired during chronic alcohol ingestion. Studies of the effect of alcohol on cell cultures will indicate whether cellular mechanisms are sufficient to induce membrane tolerance and dependence. The effect of alcohol on membrane surface charge, and particularly on Ca2+ binding and distribution, will be investigated in relationship to the role of the dielectric constant in the effect of alcohol on Ca2+ metabolism. It is hoped that this investigation will lead to a better understanding of the mechanism of the adaptation of membranes to chronic alcohol ingestion and the development of tolerance and dependence. Such knowledge may lead to new therapeutic strategies in combating chronic alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA007238-04
Application #
3110953
Study Section
Biochemistry, Physiology and Medicine Subcommittee (ALCB)
Project Start
1987-03-01
Project End
1991-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Hahnemann University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Rottenberg, H; Bittman, R; Li, H L (1992) Resistance to ethanol disordering of membranes from ethanol-fed rats is conferred by all phospholipid classes. Biochim Biophys Acta 1123:282-90
Thayer, W S; Rottenberg, H (1992) Comparative effects of chronic ethanol consumption on the properties of mitochondria from rat brain and liver. Alcohol Clin Exp Res 16:1-4
Rottenberg, H; Marbach, M (1992) The effect of alkanols on Ca2+ transport in brain mitochondria. Cell Calcium 13:41-7
Rottenberg, H (1992) Probing the interactions of alcohols with biological membranes with the fluorescent probe Prodan. Biochemistry 31:9473-81
Rottenberg, H; Marbach, M (1991) Alcohol stimulates Na+/Ca2+ exchange in brain mitochondria. Life Sci 48:987-94
Rottenberg, H; Marbach, M (1990) The Na(+)-independent Ca2+ efflux system in mitochondria is a Ca2+/2H+ exchange system. FEBS Lett 274:65-8
Rottenberg, H (1990) Decoupling of oxidative phosphorylation and photophosphorylation. Biochim Biophys Acta 1018:1-17
Rottenberg, H; Marbach, M (1990) Regulation of Ca2+ transport in brain mitochondria. I. The mechanism of spermine enhancement of Ca2+ uptake and retention. Biochim Biophys Acta 1016:77-86
Rottenberg, H; Marbach, M (1990) Regulation of Ca2+ transport in brain mitochondria. II. The mechanism of the adenine nucleotides enhancement of Ca2+ uptake and retention. Biochim Biophys Acta 1016:87-98
Rottenberg, H; Marbach, M (1989) Adenine nucleotides regulate Ca2+ transport in brain mitochondria. FEBS Lett 247:483-6