Question

Ethanol metabolism starves the cell of NAD+ and increases production of reactive oxygen species. What will be the effect on TCA cycle, PPP, glycogen metabolism, and beta-oxidation?

Answer 1

Ans: As given in the question that ethanol metabolism starves the cell for NAD+ which means that NADH/NAD+ ratio will increase because of ethanol metabolism. The metabolism of ethanol in vivo takes place almost exclusively in the liver. The major ethanol metabolizing system in the liver in vivo is ADH, particularly at low alcohol concentrations. The most important feature of these reactions is the production of NADH at the expense of NAD+ .

Ethanol metabolism effect on TCA cycle: Whereas glucose is oxidized to pyruvate by anaerobic glycolysis, pyruvate is oxidized aerobically by the tricarboxylic acid (TCA) cycle. Unlike glycolysis which takes place in the cytosol compartment of the cell, the TCA cycle occurs in the mitochondria and is, therefore, associated with the production of a large amount of energy in the form of ATP. A correlation between the effects of ethanol on the redox state and the production of carbon dioxide, and that the change in mitochondrial [NAD+ ]/ [NADH] ratio led to the inhibition of the kreb cycle.

The mechanism(s) by which ethanol inhibits the TCA cycle is not clearly understood. The accumulation of NADH during ethanol oxidation decreases the steady state concentration of pyruvate.3 This limits the activity of the gluconeogenic enzyme pyruvate carboxylase which produces oxaloacetate. Ethanol, by lowering the concentration of pyruvate, can therefore inhibit the TCA cycle by decreasing oxaloacetate formation.

The second mechanism (involving the change in the redox state of the mitochondrial NAD+ couple) may also involve an increase in the malate/ oxaloacetate ratio, an effect that is expected to inhibit the cycle.

Ethanol metabolism effect on Pentose Phosphate Pathway: Very little work has been done on the possible effect of ethanol on this pathway. This is largely due to the belief that ethanol only affects the redox state of the NAD+ couple which is not used by the pathway. However, ethanol has now been shown to increase the ratio of [NADPH]/ [NADP+ ] in rat liver both after acute4 and chronics'6 administration. The mechanism by which ethanol increases the above ratio by increasing [NADPH] is, at present, not clearly understood. It is interesting that ethanol added to liver slices inhibits glucose oxidation by the pentose phosphate pathway.

Ethanol metabolism effect on Glycogen metabolism: Ethanol releases catecholamines. Catecholamines stimulate glycogenolysis in muscle and lipolysis in adipose tissue and thus increase the gluconeogenic substrate supply to the liver. This means that ethanol metabolism increases glycogen metabolism.

Ethanol metabolism effect on beta-oxidation: The increase in the NADH:NAD⁺-ratio caused by alcohol metabolism directly inhibits mitochondrial β-oxidation. This effect is thought to be predominantly mediated by the NAD+ reducing enzyme, 3-hydroxy-CoA dehydrogenase, the final step in generating acetyl-CoA during β-oxidation.

Hence ethanol metabolism inhibits beta-oxidation of fatty acids.