Alcohol Intolerance and ToxicityHangover biochemistry, cancer risk, Asian woes, and TV shows
There are several enzymes involved in helping our bodies detox from alcohol. These enzymes and/or subsequent breakdown products are responsible for many of the common occurrences we experientially associate with it.Break It Down
The liver enzyme alcohol dehydrogenase
(ADH) helps metabolize ethanol (EtOH -- the type of alcohol for consumption) to acetaldehyde, which in turn is metabolized by acetaldehyde dehydrogenase
(ALDH) into a less harmful compound, acetic acid (vinegar).
EtOH →(via ADH)→ acetaldehyde →(via ALDH)→ acetic acid
Of course, there are other enzymes that contribute as well, such as the cytochrome P450 system that oxidizes organic molecules and multiple diverse substrates.Mechanism of a Breath-alcohol Test
Breathalyzers do not measure blood alcohol content directly. Instead, the electrochemical devices detect the presence of volatile exhaled ethanol and its breakdown products. There are several ways to do this through chemical reactions and photocell detectors, infrared spectroscopy, and fuel cell technology.
For the fuel cell method, ethanol in the breath is oxidized to acetic acid by platinum at the anode, while oxygen is reduced at the cathode. The resulting electric current is "interpreted" by a calibrated sensor, microprocessor, and display to output a number.One Yeast's Waste is Another Person's Treasure
The first ever isolated ADH was in baker's yeast (Saccharomyces cerevisiae)
in 1937. The ability to produce high concentrations of ethanol from sugar was believed to initially evolve in yeast and may have provided a survival advantage to eliminate its competition. During alcoholic fermentation, ethanol (beer!) and carbon dioxide (rising bread!) are produced as metabolic waste products.The Hangover: Starring Acetaldehyde
An accumulation of acetaldehyde -- the intermediate metabolite referred to above -- is a large contributor to "hangover" symptoms.
For this reason, the drug disulfiram has been used to deter alcohol abuse in some individuals because it inhibits ALDH. To phrase it mildly, it provides strong negative reinforcement to minimal alcohol intake (i.e., it greatly magnifies hangover effects!) In one study from 2006, after disulfiram was incorporated into a comprehensive treatment program and administered under medical supervision, abstinence rates improved to over 50% .Genetic Variation and Drinking Behavior
A common stereotype is that Asians light up like Christmas trees and become red-faced beacons after ingesting relatively modest-to-little amounts of ethanol.
The well-known alcohol-induced flush reaction is facilitated by a mutation in the structural gene that encodes for a faulty type of aldehyde dehydrogenase, ALDH2 .
From a clinical standpoint, ALDH2 deficiency is one of the strongest genetic factors that influence drinking behavior and risk of alcoholism. Without ALDH2, individuals may have consistently more unpleasant experiences with ethanol and a stronger response to acetaldehyde, ultimately encouraging minimal alcohol use or avoidance.
allele is dominant over the wild-type allele ALDH2*1
and impairs alcohol detoxification by reducing both the enzyme's catalytic efficiency and overall half-life.
Compared to Caucasians, 90% of Orientals have a 100-times more
active ADH variant (the first enzyme in our biochemical equation above), and approximately 50% have only ALDH1 and are missing ALDH2 altogether (the second enzyme in our equation above) . In other words, more acetaldehyde is produced while less is broken down, leading to greater accumulation.(Related: a Google+ post about "Population Genetics of Alcoholism" by +Peter Smalley: goo.gl/8khs6p )Cancer Risk
Chronic alcohol consumption is a major risk factor with causal association for upper aero-digestive tract cancers of the mouth, larynx, pharynx, esophagus, and liver with less but still present risks for colorectal and breast cancers [4-6]. Recurring alcoholic pancreatitis increases risk of pancreatic cancer as well.
Acetaldehyde appears to be the main culprit for alcohol-associated carcinogenesis. The same molecule contributing to that pesky hangover is toxic, mutagenic, and carcinogenic -- it induces inflammation, interferes with DNA synthesis and repair, and hinders the immune system.Name Your Poison
Similarly, other substances are modified by the same set of enzymes and yield toxic metabolites too.
Methanol is the simplest alcohol with one less carbon atom or bridging methylene group than ethanol: CH3-OH vs. CH3-CH2-OH. Its largest use by far is during manufacture of other chemicals and products like plastics, plywood, paints, and textiles.
During Prohibition, bootlegged liquor ("moonshine") caused health problems either through contaminants or more frequently through unscrupulous distillers who added cheap methanol to boost its strength and to save costs. ADH converts methanol to formaldehyde -- popularly known as being used to preserve biological tissue samples and cadavers -- and then to formic acid by ALDH. Formic acid is the main cause of methanol toxicity , including the destruction of the optic nerve to cause blindness.
Ethylene glycol (HO-CH2-CH2-OH) is used in antifreeze, among other products. On occasion, open bottles of antifreeze may be consumed by children and pets due to its appealing natural sweetness. Ethylene glycol is metabolized by ADH to compounds that can cause kidney failure and other organ damage.Self-medicating in More Ways Than One
Interestingly, ethanol can potentially work as an early "antidote" to methanol and ethylene glycol poisoning because it occupies the active sites of ADH. Ethanol competitively inhibits the breakdown of those other substances, theoretically allowing them to be excreted before they form more toxic byproducts.
Although treating with ethanol is generally not recommended nor sufficient and would not be used in a hospital (rather, use of intravenous hydration, supportive care, and possibly dialysis instead), fomepizole is a drug that achieves the same effect by competitively inhibiting ADH too.
This scenario appeared in an episode from the TV series "House, M.D." where Dr. House gets a prisoner drunk with vodka to empirically mitigate the suspected self-induced methanol poisoning .References:
Disulfiram Reaction - http://en.wikipedia.org/wiki/Disulfiram
The Mutation in the Mitochondrial Aldehyde Dehydrogenase (ALDH2) Gene Responsible for Alcohol-induced Flushing Increases Turnover of the Enzyme Tetramers in a Dominant Fashion (full text) - http://www.jci.org/articles/view/119007/pdf
Molecular Abnormality of an Inactive Aldehyde Dehydrogenase Variant Commonly Found in Orientals (full text) - http://www.pnas.org/content/81/1/258.full.pdf+html
Alcohol and Cancer (2004 full text) - http://alcalc.oxfordjournals.org/content/39/3/155.long
Alcohol and Cancer (Lancet Oncology 2006 abstract) - http://www.ncbi.nlm.nih.gov/pubmed/16455479
Alcohol and Cancer: Genetic and Nutritional Aspects (abstract) - http://www.ncbi.nlm.nih.gov/pubmed/15070439
Lack of a Role for Formaldehyde in Methanol Poisoning (full text) - http://www.whilesciencesleeps.com/pdf/274.pdf
House, M.D. Season 2 Episode 1 - http://www.housemd-guide.com/season2/201acceptance.php#ScienceEveryday
/ +ScienceSunday #Alcohol #Biochemistry #MetabolismImage is from Wikimedia Commons and in public domain.