Ethanol

File:Ethanol-structure.svg - Wikimedia Commons

Source 1,2

  • Ethanol is a renewal biofuel because it is made from biomass. It is a clear, colorless alcohol made from biomass feedstocks
    • Feedstock: raw materials used to make a product
    • There are two production methods of ethanol:
    1. Produced from starch based crops (i.e. corn, barley) via dry- or wet-mill processing
      • Most common source of ethanol
      • Dry mill processing accounts for 90% of production
    2. Produced from cellulosic feedstocks (i.e. grass, wood, and crop residues) via biochemical or thermochemical processes
      • Much more involved process
      • Not common in the USA

Biotransformation 3,4

  • Ethanol has both hydrophilic and lipophilic properties, which allows it to quickly pass though biological barriers
  • Over 95% of ethanol undergoes biotransformation, with the remaining 5% excreted unchanged via urine and exhaled air

  • The main two sites of ethanol biotransformation are the stomach lining and the liver, with the vast majority occurring in the liver. The following dives deeper into hepatic metabolism of ethanol
  • Ethanol is oxidized to acetaldehyde via class I alcohol dehydrogenase (ADH), which requires cofactor NAD+ and zinc. When ethanol is converted to acetaldehyde, NAD+ is reduced to NADH
    • Class I ADH has the highest affinity for ethanol
    • Classes II & III come into play when ethanol concentrations are very high
      • They bind to ethanol more readily in this state to help process it
  • Acetaldehyde leaves the liver and enters circulation, where it can exert toxic effects on other organs
    • In order to decrease the amount of acetaldehyde that can enter circulation, aldehyde dehydrogenase (ALDH) that is located in hepatocyte mitochondria, metabolizes it to acetate
      • This process requires NAD+ and the reduction of NAD+ to NADH
  • Acetate will then leave the liver for circulation or stay in the liver
    • Either path acetate takes, it will be processed either into CO2 or Acetyl-CoA, respectively

Toxicokinetics 5

  • Human CYP2E1 is effective in production of reactive oxygen intermediates from ethanol that cause lipid peroxidation
  • Ethanol induces the release of endotoxin from gram-negative bacteria in the gut, which is then taken up by Kupffer cells, causing the release of inflammatory mediators, which are cytotoxic to hepatocytes and chemoattractants for neutrophils
  • Alcoholic cardiomyopathy that results from decreased synthesis of cardiac contractile proteins, attack of oxygen radicals, increases in endoplasmic reticulum Ca2+-ATPase, and antibody response to acetaldehyde-protein adducts
  • Increased consumption of ethanol appears to deplete antioxidants and increase the risk of hemorrhagic and ischemic strokes

 

Carcinogenicity 5

  • Chronic ethanol consumption may promote carcinogenesis by the following:
    1. Production of acetaldehyde
    2. Induction of CYP2E1 with conversion of pro-carcinogens to carcinogens
    3. Depletion of S-adenosylmethionine, and consequently, global DNA hypomethylation
    4. Increased production of inhibitory guanine nucleotide regulatory proteins and components of extracellular signal-regulated kinase-mitogen-activated protein kinase signaling
    5. Accumulation of iron and associated oxidative stress
    6. Inactivation of the tumor suppressor gene BRCA1 and increased estrogen responsiveness
    7. Impairment of retinoic acid metabolism
  • Cirrhosis or other liver damage is caused by the bioactivation of carcinogens

 

Mechanism of Action 6

  • Mimics GABA’s effect on the brain, binding to GABA receptors and inhibiting neuronal signaling.
  • Inhibits the major excitatory neurotransmitter, glutamate, particularly at the N-methyl-d-aspartate (NMDA) glutamate receptor
  • Releases other inhibitors, such as dopamine and serotonin
  • Increases the amount of dopamine in the nucleus accumbens area of the brain, aka the “reward centers.”

Target organs

  • Liver
  • Brain/Nervous System
  • Kidneys
  • Cardiovascular System
  • Pancreas
  • GI Tract
  • Fetus (in utero)

Signs and symptoms of toxicity 7

  • Abdominal pain
  • Confusion, slurred speech
  • Internal (stomach and intestinal) bleeding
  • Slowed breathing
  • Stupor (decreased level of alertness), even coma
  • Unsteady walking
  • Vomiting, sometimes bloody
  • Chronic alcohol overuse can lead to additional symptoms and multiple organ failure

Genetic susceptibility or heritable traits 8

  • ADH1B and ALDH2
    • These genes have the strongest known affects for the risk of alcoholism
  • GABRA2, CHRM2, KCNJ6, and AUTS2
    • Variants of these genes impact the risk for alcoholism
  • Animal studies demonstrate genetic liability
    • Mice and rats have been selectively bred for many traits associated with alcohol dependence, including alcohol preference, alcohol sensitivity, and withdrawal sensitivity
  • The ability to genetically select for these traits demonstrates that there are genetic bases for them, and that different genes contribute to different aspects of the phenotype
  • Taken together, there is overwhelming evidence that genetic variations contribute to the risk for alcohol dependence

Treatments 7

  • Mostly consists of supportive care including, but not limited to:
    • Pumping the stomach to remove ethanol, if possible
    • Establishment of an airway in the unconscious patient
    • Dextrose administration in the event of hypoglycemia
    • Vitamin administration
    • Oxygen therapy
    • Antiemetics
    • ECG Monitoring
    • IV fluids unless contraindicated

Biomarkers 9

  • Direct biomarkers
    • Products of direct ethanol biotransformation
    • Represent unequivocal evidence of ethanol exposure
    • Include:
      • ethyl glucuronide (EtG)
      • ethyl sulfate (EtS)
      • phosphatidylethanol (PEth)
      • fatty acid ethyl esters (FAEEs)
  • Non Traditional Matrix Types
    • Urine
    • Dried blood spots
    • Nails
    • Hair

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References

  1. “Ethanol Explained.” U.S. Energy Information Administration, 2021, www.eia.gov/energyexplained/biofuels/ethanol.php.
  2. “Alternative Fuels Data Center: Ethanol Production.” Alternative Data Fuels Center, U.S. Department of Energy, afdc.energy.gov/fuels/ethanol_production.html. Accessed 1 July 2021.
  3. Cederbaum, Arthur I. “Alcohol metabolism.” Clinics in liver disease vol. 16,4 (2012): 667-85. doi:10.1016/j.cld.2012.08.002
  4. Zakhari, Samir. “Overview: how is alcohol metabolized by the body?.” Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism vol. 29,4 (2006): 245-54.
  5. Klaassen, Curtis D. “Toxic Effects of Solvents and Vapors.” Casarett & Doull’s Essentials of Toxicology, edited by John B. Watkins, 3rd ed., McGraw Hill, 2015, pp. 368–69.
  6. Bardi, Jason Socrates. “The Scripps Research Institute – News and Views.” One Night in San Diego: Tragedy of Alcohol Abuse Drives TSRI Researcher’s Work, 25 Feb. 2002, www.scripps.edu/newsandviews/e_20020225/koob2.html.
  7. “Ethanol Poisoning.” Medline Plus, 2021, medlineplus.gov/ency/article/002644.htm.
  8. Edenberg, Howard J, and Tatiana Foroud. “Genetics and alcoholism.” Nature reviews. Gastroenterology & hepatology vol. 10,8 (2013): 487-94. doi:10.1038/nrgastro.2013.86
  9. Shu, PhD, Irene. “Direct Ethanol Biomarkers in Non-Traditional Matrices.” AACC, 1 Sept. 2016, www.aacc.org/cln/articles/2016/september/direct-ethanol-biomarkers-in-non-traditional-matrices.