From Pre-drinks to Hangover: The Acute Consequences of Ethanol Metabolism

I’ve been very quiet lately. Have some exams to revise but since it’s nearly Christmas time I thought I’d share an old essay I wrote during my post grad days on the consequences of alcohol intake. Not strictly sports medicine i’ll admit but always good to think about in the context of general health. Disclaimer- this is about 6 years old now, so I’m sure there will be updated information out there, but for now I think it makes for an interesting read. Enjoy!

 

The majority of people are aware of the consequences involved in a night of heavy alcohol consumption. There is the good: the loss of social inhibition, the feelings of empowerment and mild euphoria, an increase in confidence and those epiphany moments you can only achieve after the clock strikes twelve. There is also the bad: the lack of coordination and balance, we lose our ability to rationalise situations, we lose our memories, vomit, perhaps fall unconscious and of course there is the dreaded hangover and all its associated symptoms. But what are the metabolic mechanisms that underlie these consequences?

 

Alcohol Metabolism

 

A very small amount of alcohol, about 2-10%, is eliminated from the body in urine or breath (Morgan and Ritson, 2010), the majority must be metabolised to be cleared by the body. Metabolism occurs mainly in the liver, and involves two main steps. The first is catalysed by the enzyme alcohol dehydrogenase (Stryer, 2011).  Here ethanol is oxidized to acetaldehyde (Wrenn et al, 1991), and involves the reduction of NAD+to NADH (McGuire et al, 2006).

 

CH3CH2OH + NAD+  >  CH3CHO + NADH + H+

 

Acetaldehyde acts as a general body vasodilator by its activation of release of NO from endothelial cells, and is responsible for the flushing associated with drinking, due to vasodilation of capillaries at the skin surface (Kuhlmann et al, 2004). Acetaldehyde is a toxic substance, and high levels can lead to nausea, headaches and faintness, as well as palpitations (Ashworth and Gerada, 1997). It is interesting that different isoforms of acetaldehyde dehydrogenase can be found across different ethnic groups. It is well documented that many people with Asian origins have a lower tolerance to alcohol consumption, showing a greater flush response after only small amounts of alcohol have been consumed and reporting severe hangover symptoms following a binge. Many studies have looked into these racial differences, including one by Teng (1981) who showed that 50% of Chinese people studied contained a deletion in one of the gene loci encoding acetaldehyde dehydrogenase, which results in an inefficient enzyme being produced.

An anti-alcoholic drug, Antabuse (Disulfram) has been developed that promotes severe alcohol related symptoms and discourages drinking. This inhibits the action of acetaldehyde dehydrogenase leading to a build-up of toxic acetaldehyde (Kristenson, 1995).

 

The second step is the conversion of acetaldehyde to acetate, by acetaldehyde dehydrogenase (Kraut and Kurtz, 2008)

 

CH3CHO + NAD+ + H2O   >   CH3COO+NADH + 2H+

 

These processes combined lead to an increase in NADH levels, a key factor in the development of negative symptoms involved in alcohol consumption.

The NADH:NAD+ratio increases as NAD+is being reduced faster than NADH is oxidised, as NADH oxidation occurs during the metabolism of pyruvate. However, the levels of pyruvate being produced are lowered through the following two mechanisms. NADH feeds back on the glycolysis pathway, see Fig.1, leading to a reduction in the amount of pyruvate produced (Wilson et al, 1981).

 

alcohol1.png
EnterFigure 1NADH favours the return reaction of 1,3-Bisphosphoglycerate to Clyceraldehyde 3-phosphate during the Glycolysis pathway, reducing the overall amount of pyruvate produced further along the pathway. (Taken and adapted from Stryer, 2011. Fig. 16.2) 

Secondly, lactic acid is normally converted into pyruvate by the reduction of NAD+, facilitated by the enzyme lactate dehydrogenase in a reversible reaction (Stryer, 2011). Due to the high presence of NADH, the reaction equilibrium shifts to favour lactate production. This leads to less pyruvate available for gluconeogenesis, and so throughout a drinking session, blood sugar levels drop. As the brain is the main consumer of glucose produced in the liver (Kumar and Clark, 2009) most effects are neurological, it is another cause of nausea and vomiting associated with binge drinking. In response to the hypoglycaemia the body craves carbohydrate based foods, hence the desire for fast food experienced by many people at the end of a night out.

As mentioned, there is a decrease in the amount of lactic acid converted to pyruvate, and lactic acid builds up. This can result in lactic acidosis. An increased respiratory rate, to induce respiratory alkalosis, is usually sufficient to counter-act the amount of acidosis that occurs due to an alcohol binge, although venoconstriction can occur, as well as arteriolar vasodilation, resulting in hypotension (Kumar and Clark, 2009), this can have the secondary consequence of tachycardia.

Finally, NADH will also encourage fatty acid synthesis in the liver, leading to accumulation of fatty tissue (Leiber and Schmid, 1960). Short term this has very little effect, and can be reversed by abstaining from alcohol.

 

Alcohol and the Krebs Cycle

 

Acetate is converted into acetyl CoA via the enzyme thiokinase. This involves the movement of a phosphate group from ATP, which allows the joining of acetate to coenzyme A (Stryer, 2011).

Acetate + Coenzyme A + ATP    >   acetyl CoA + AMP + PPi

 

Acetyl CoA would then normally be fed into the Kreb’s cycle, and while this initially happens, the increased NADH levels inhibit the action of two enzymes within the cycle, isocitrate dehydrogenase (converts isocitrate to α-ketoglutarate) and α-ketoglutarate dehydrogenase (converts α-ketoglutarate to succinyl-CoA), see Fig 2.This will halt all reactions within the cycle, leading to a build-up of acetyl CoA, but also α-ketoglutarate, a ketone body. This may result in ketoacidosis, and can be further aggravated by loss of fluids should vomiting be induced due to alcohol (Thomsen et al, 1995). Acute ketoacidosis will rarely cause major problems in a non-alcoholic, but may add to the symptoms of lactic acidosis, such as hypotension and tachycardia.

alcohol2
Figure 2  The Citric Acid Cycle.The enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase (shown by arrows) are inhibited when NADH levels are high. This will slow down the cycle and acetyl CoA will build up, as this normally feeds into the cycle.

The Hangover

 

The final stages associated with binge drinking are well known, but the mechanisms underlying the hangover are poorly understood, and very little research has been done to resolve this. It is unusual that there should be such an array of symptoms afterethanol and its metabolites have been cleared from the body. There is a long held belief that dehydration accounts for many of the symptoms, although there is conflicting evidence for this. New evidence is emerging for a neurological based cause (discussed below) of some of the symptoms. It is likely a combination of this and dehydration that makes people feel terrible after drinking.

 

Neurological Effects

 

Parallel to the effects caused by the metabolism of ethanol, there are also a number of neurological responses, which are the direct effect of ethanol acting on receptors and ion channels within the central nervous system (CNS). The specific effects are variable depending on the region of the CNS involved, but fundamentally, ethanol acts to slow down electrical activity in the brain. For example, Basile et al (1983), showed a decrease in the firing rate of Purkinje cells when exposed to ethanol. This reduces reaction time, cognition and perception, and gives us euphoric sensations. Like all aspects of neurology, studying the effects of ethanol in the brain is a complicated process, and many of these mechanisms are still unknown, for example, the processes underlying memory loss. However some evidence suggests the immune response triggered by ethanol leads to an upregulation of cytokines, which may bind to receptors in the hippocampus, thus preventing these receptors being available for long term potentiation and memory formation (Kim et al, 2003). Continued work into the field is revealing more aspects of the neurological effects and recent work has shown that the sedative effects of alcohol may be due to its action on α5-subunit-containing γ-aminobutyric acid type A receptors in the hippocampus (Martin et al, 2011). The same receptor may also be involved in memory loss. (Nutt et al, 2007) Exactly how this works is still unknown, but a selective inverse agonist for this receptor was shown to improve the memory of subjects after intoxication. These are the first experiments that show simply blocking the activity of certain receptors can offset some of the effects of alcohol, and provide and interesting avenue for further research.

It has also been proposed that the upregulation of cytokines may be responsible for the core symptoms of a hangover, including sickness, fatigue and a lack of interest (Dantzer et al, 1998).  Ethanol and its metabolites have been cleared by this point but the immune response remains, making this a popular theory.

 

Future Considerations

 

In an interesting side note, Professor Nutt has carried research into finding alcohol substitutes, based principally around benzodiazepines, which inhibit GABA receptors. This research involves the discovery of a complimentary substance that can be taken later and will remove all trace of the original substance, thus eliminating the hangover. If this hangover-less substance becomes available to the market, in place of ethanol, perhaps future research into the treatment of the hangover will become a mute point.

While the metabolic effects of alcohol are fairly well documented, effective treatments for the dreaded hangover are still largely unavailable. More research into the underlying mechanisms of alcohol breakdown and the effect that metabolites have on the body’s systems should reveal potential therapy targets that may make many of the symptoms of ethanol consumption a thing of the past. This same principal applies to the effect ethanol has on the CNS, although this presents as a serious challenge due to infinite complexity of the human nervous system.

 

References

 

Ashworth M and Gerada C. 1997. ABC of mental health: Addiction and dependence—II: Alcohol. British Medical Journal 315: 358.

 

Basile A, Hoffer B, Dunwiddie T. 1983. Differential sensitivity of cerebellar Purkinje neurons to ethanol in selectively outbred lines of mice: maintenance in vivoindependent of synaptic transmission. Brain Research 264: 69-78.

 

Berg JM, Tymoczko JL, Stryer L. 2011. Biochemistry. 7thed. USA: W. H. Freeman and Company.

 

Dantzer R, BluthéR-M, LayéS, Bret-Dibat J-L, Parnet P, Kelley KW. 2006. Cytokines and sickness behavior. Annals of the New York Academy of Sciences 840: 586-590.

 

Kim D-J, Kim W, Yoon S-J, Choi B-M, Kim J-S, Go HJ, Kim Y-K, Jaeseung J. 2003. Effects of alcohol hangover on cytokine production in healthy subjects. Alcohol 31: 167-170.

 

Kraut JA and Kurtz I. 2008. Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management.Clinical Journal of the American Society of Nephrology 3: 208-225.

 

Kristenson H. 1995. How to get the best out of antabuse. Alcohol & Alcoholism 30:775-783.

 

Kuhlman CRW, Li F, Lüdders DW, Schaefer CA, Most AK, Backenköhler U, Neumann T, Tillmanns H, Waldecker B, Erdogen A, Wiecha J.  2004. Dose-Dependant Activation of Ca+-activated K+Channels by Ethanol Contributes to Improved Endothelial Cell Functions. Alcoholism: Clinical and Experimental Research 28: 1005-1011.

 

Kumar P and Clark M. 2009. Clinical Medicine. 6thed. Spain: Saunders Elsevier.

 

Lieber CS and Schmid R. 1960. The Effect of Ethanol on Fatty Acid Metabolism; Stimulation of Hepatic Fatty Acid Synthesis in vitro. Journal of Clinical Investigation 40: 394-399.

 

Martin LJ, Zurek AA, Bonin RP, Oh GHT, Kim JH, Mount TJ, Orser BA. 2011. The sedative but not memry-blocking properties of ethanol are modulated by α5-subunit-containingγ-aminobutyric acid type A receptors. Behavioural Brain Research 217: 379-385.

 

McGuire LC, Cruickshank AM, Munro PT. 2006. Alcoholic Ketoacidosis. Emergency Medicine Journal 23: 417-420.

 

Morgan MY and Ritson EB. 2010. Alcohol and Health. 4thed.London: The Medical Council on Alcohol.

 

Nutt DJ, Besson M, Wilson SJ, Dawson GR, Lingford-Hughes AR. 2007. Blockade of alcohol’s amnestic activity in humans by an a5 subtype benzodiazepine receptor inverse agonist. Neuropharmacology 53: 810-820.

 

Teng Y-S. 1981. Human Liver Aldehyde Dehydrogenase in Chinese and Asiatic Indians: Gene Deletion and its Possible Implications in Alcohol Metabolism. Biochemical Genetics 19: 107-114.

Thomsen JL, Felby S, Theilade P, Nielson E. 1995. Alcoholic ketoacidosis as a cause of death in forensic cases. Forensic Science International 75: 163-171.

Wilson NM, Brown PM, Juul SM, Prestwich SA, Sönksen. 1981. Glucose turnover and metabolic and hormonal changes in ethanol-induced hypoglycaemia. British Medical Journal 282: 849-853.

 

Wrenn KD, Slovis CM, Minion GE, Rutkowski R. 1991. The Syndrome of Alcoholic Ketoacidosis. American Journal of Medicine 91: 119-128.