Metabolism and effects of alcohol in humans

Alcohol in drinks  (ethanol) is metabolised in humans primarily in a  pathway involving two enzymes—alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). First, ADH metabolises the alcohol to acetaldehyde, which unfortunately is a highly toxic substance and carcinogen. Then, acetaldehyde is further metabolised to acetate, which then is broken down into water and carbon dioxide which are excreted in the urine and breath.

Although acetaldehyde is short-lived in the body it has the potential to cause significant damage. This is particularly evident in the liver, where the bulk of alcohol metabolism takes place in the hepatocytes. Some alcohol metabolism also occurs in other tissues, including the pancreas GI tract and the brain, causing damage to cells and tissues there.

At high concentrations, alcohol is eliminated at a high rate because of the presence of enzyme systems with high activity levels. This is a linear relationship. ( one unit alcohol or 8grams per hour ). This oxidation process involves an intermediate carrier of electrons, nicotinamide adenine dinucleotide (NAD+), which is reduced by two electrons to form NADH. As a result, alcohol oxidation generates a highly reduced cell cytoplasm environment. In other words, these reactions leave the liver cells in a state that is particularly vulnerable to damage from the byproducts of ethanol metabolism, such as free radicals and of course the  acetaldehyde.

Acetaldehyde produced by the alcohol oxidation is rapidly metabolised to acetate, mainly by ALDH in the cells mitochondria, to form acetate and NADH. Acetaldehyde has the capacity to bind to proteins such as enzymes, microsomal proteins, and DNA  and is carcinogenic.

Alcohol is one of the most-used drugs in the world. Millions of people enjoy the tipsy feeling it produces, especially in social gatherings where a little booze seems to make the good times roll.

Ethanol, a remarkably simple and small molecule C2H5OH.

It permeates the cells of our body including the  brain within minutes of consumption. For most molecules, it’s not easy to get into the brain. There is a barrier called the blood brain barrier or BBB that protects the brain from foreign substances that could potentially harm it. For the brain, there is no barrier to ethanol. Ethanol crosses the blood-brain-barrier very easily due to its chemical characteristics—although it is somewhat polar, it is also lipophilic and so it mixes easily with the fat in the membrane. Unlike other drugs that affect particular brain regions or act on specific receptors, alcohol  just  goes all over it. Its main effect is as a depressant, meaning it generally suppresses neural activity in the brain. It amplifies the effects of brain chemicals that inhibit neural activity — GABA and glycine — by acting on the same receptors those neurotransmitters bind to. At the same time, alcohol inhibits the effects of excitatory brain chemicals, producing a double-whammy of reducing brain activity. But it is not so simple. As most people who drink may know, alcohol has a biphasic effect: initially and in low doses, it produces a buzz where we feel stimulated and disinhibited like we can dance or converse forever, before sleepiness settles in. fMRI neuroimaging scanning  shows alcohol may cause us to become disinhibited by dampening activity in parts of our frontal cortex, which is important for executive control functions such as inhibiting behaviours we don’t want to do. By inhibiting our inhibitions, alcohol makes us feel more stimulated. Being pleasantly buzzed also releases dopamine and increases activity in the striatum part of the basal ganglia , a key brain region associated with rewarding stimuli. Alcohol affects the emotion centres of the brain as well particularly the amygdala another part of the basal ganglia’s ( a complex and crowded area).

However not all people enjoy alcohol as much Some people especially from the East don’t. They suffer from an alcohol flush reaction, which  is a condition in which a person develops flushes or blotches or erythma daily on the face after an alcohol drink. The reaction is the result of an accumulation  of  its breakdown product acetaldehyde caused by a aldehyde dehydrogenase deficiency. Approximately 30 to 50% of Chinese, Japanese, and Koreans show this and suffer nausea headaches and an increased heart rate. Around 20–30% of East Asians carry the rs671 (ALDH2*2) allele on chromosome 12, which results in a less functional aldehyde enzyme. The rs671 allele is native to East Asia. Analysis correlates the rise of this allele to the spread of rice cultivation geographically and temporally. The reasons for this positive selection are not known, but it has been suggested that elevated concentrations of acetaldehyde may have conferred protection against certain parasitic infections, such as Entamoeba histolytica  is an parasite common in rice paddies where wastewater and human and animal excreta are used as fertiliser ( in poor areas this results in up to 30% increases in crop yields). Currently it is estimated Entamoeba histolytica  infects up to 50 million people worldwide and kills more than 55,000 people  yearly.

If that was not bad enough in around 80% of East Asians, the accumulation of acetaldehyde is worsened by another gene variant; in this case the allele ADH1B*2, which results in the  ADH enzyme converting alcohol to acetaldehyde more quickly!