Factors Impacting Ethanol Absorption & Metabolism: Gastric Emptying, First Pass Effect, & , Papers of Medical Biochemistry

Download Factors Impacting Ethanol Absorption & Metabolism: Gastric Emptying, First Pass Effect, & and more Papers Medical Biochemistry in PDF only on Docsity!

ALCOHOL METABOLISM

Alcohol metabolism follows a short pathway of oxidation to acetaldehyde, followed by further oxidation of the acetaldehyde to acetate. Alcohol is metabolized in the body mainly by the liver. When we ingest ethanol there are factors that affect the rate at which ethanols absorb. One of those is the gastric emptying rate or the rate at which are stomach empties its contents the other is ethanol concentration so with the gastric emptying rate and empty stomach during times of fasting would actually increase the gastric emptying so on empty stomach when we ingest ethanol we actually increase the rate of absorption because the gastric emptying rate is increased. On the other hand any food like carbohydrates fats and proteins will actually reduce the way to gastric emptying which would reduce the rate of alcohol or ethanol absorption. When ethanol is absorbed, it enters into the portal vein then travels to deliver now in the liver it undergoes a specific effect known as the first pass metabolism. First pass effect is metabolism of ethanol before it reaches the system it circulation in this occurs in a liver, this is actually higher in men than women. This is one of the reasons why men on average can tolerate alcohol better than women. So when ethanol does get absorbed into a cell it happens by passive diffusion itself is related to the ethanol concentration which means that with increasing ethanol concentration you have an increase rate of diffusion, so all of these factors affect absorption of ethanol. When ethanol is absorbed in the body there are two primary locations where ethanol is metabolize one is in the lining of the stomach however the vast majority of ethanol metabolism occurs in the liver. The metabolism of ethanol begins with the enzyme alcohol dehydrogenase or adh which process the ethanol into acetaldehyde now this enzyme requires an NAD+ as a cofactor and what it does is when the ethanol was processed in the acetaldehyde any deposit actual reduced to NADH. Also alcohol dehydrogenase requires zinc as a cofactor for its function as well. There are several classes of alcohol dehydrogenase in class when is by far the most important in ethanol metabolism is class one, it has the highest affinity for ethanol so the majority of ethanol is metabolize at class one alcohol dehydrogenase in the liver. However, class two and three both have important roles, especially during high concentrations of ethanol so class 2 & class 3 alcohol dehydrogenase actually have a low affinity for ethanol but when ethanol concentration is very high both

fact it becomes very important when ethanol concentrations are very high so normally most of ethanol metabolism occurs with alcohol dehydrogenase but when we have situations where ethanol concentration are very high this enzyme becomes extremely important to remove excess ethanol. Another important aspect is that it produces reactive oxygen species and this can be a problem when a lot of ethanol is being metabolized. Reactive oxygen species itself specially higher levels can cause DNA damage and on other organelle problems such as mitochondrial disfunction. Its too toxic by product to the cell. When enzyme is exposed to high levels of ethanol over long periods of time it should be up- regulated so it's actually one of the mechanisms the upregulation of enzyme. It is actually wanted mechanisms by which people can gain tolerance to alcohol and it its known to actually higher in people with problem with alcoholism. So acetaldehyde can be processed with the same enzyme CYP2E1 to acetate but again a producing ROS but by majority, acetaldehyde is action metabolized by aldehyde dehydrogenase 2 acetate so CYP2E1 is not as important for metabolize. Again when we use aldehyde dehydrogenase we are again producing an NADH from the reaction and the two acetates can also be processed into acetyl CoA, this leads to high levels of NADH and high levels of acetyl CoA. This type of metabolism accounts for approximately 10% of ethanol metabolism so we will get total of ethanol metabolism from the pathway involving alcohol dehydrogenase and this pathway involving CYPE2E1 pathways together , need in a total weight of ethanol metabolism of 7 grams per hour in an average person which is about one alcoholic drink per hour. NON-OXIDATIVE ALCOHOL METABOLISM As mentioned above, ethanol is metabolized by alcohol dehydrogenase (ADH), transforming it to a toxic compound known as acetaldehyde (CH3CHO ), a close relative of formaldehyde. Acetaldehyde will be metabolized by aldehyde dehydrogenase to form acetic acid. Ethanol is mainly metabolized by oxidative alcohol metabolism, but it can also be metabolized using the non-oxidative pathway. Alcohol is non-oxidatively metabolized by at least two pathways. One leads to the formation of molecules called fatty acid ethyl esters (FAEEs) from the reaction of alcohol with fatty acids–– weak organic acids that play functional roles in human cells. The other

non-oxidative pathway results in the formation of a type of fat molecule containing phosphorus, a phospholipid known as phosphatidylethanol. FAEE are detectable in serum and other tissues after alcohol ingestion and persist long after alcohol is eliminated. The second non-oxidative pathway requires the enzyme phospholipase D (PLD), which breaks down phospholipids (primarily phosphatidylcholine) to generate phosphatidic acid (PA). This pathway is a critical component in cellular communication. PLD has a high Km for ethanol, and the enzymatic reaction does occur predominantly at high circulating alcohol concentrations. The product phosphatidylethanol is poorly metabolized and may accumulate to detectable levels following chronic consumption of copious amounts of alcohol. However, the formation of phosphatidyl ethanol occurs at the expense of the normal function of PLD, namely to produce PA, resulting in inhibited PA formation and disruption of cell signaling. Oxidative and non-oxidative pathways of alcohol metabolism are interrelated. Inhibition of ethanol oxidation by compounds that inhibit ADH, CYP2E1, and catalase results in an increase in the non-oxidative metabolism of alcohol and increased production of FAEEs in the liver and pancreas. About 1% of ethanol is metabolized by non-oxidative metabolism. CONSEQUENCE OF ALCOHOL METABOLISM Alcohol metabolism increases NADH and with alcohol dehydrogenase reaction this leads to an increase in cytosolic NADH. The aldehyde dehydrogenase reaction which occurs in mitochondria this leads to an increase in mitochondrial NADH. Ethanol metabolism eventually leads to increases in acetyl CoA as well. So increase to NADH and increase in acetyl CoA from ethanol metabolism lead to specific consequences and problems in other metabolic pathways. Since ethanol metabolism leads to an increase in NADH a decrease in NAD+ NADH ratio and an increase in acetyl CoA.There are consequences to other metabolic pathways well some of the consequences are it causes disregulation in glycolysis and some of those dysregulation can lead to lactic acidosis you can alter in effect tca cycle it can suppress gluconeogenesis and it can actually suppress fatty acid oxidation so it causes of multiple problem to other medical pathways.

to hypoglycemia. The reduction in gluconeogenesis function in the liver leads to systemic hypoglycemia. Ethanol metabolism has effects on fatty acid oxidation and synthesis. It happens because of the high levels of acetyl CoA. This pushes the reaction of the acetyl CoA carboxylase to producing more malonyl CoA. The increased acetyl CoA and malonyl CoA will lead to increased fatty acid synthesis. On the flipside the increased malonyl CoA will actually inhibit fatty acid. These will lead to triglyceride accumulation, to fatty liver disease or hepatic steatosis. FLUSH SYNDROME Alcohol metabolism happens in a relatively constant pace by the enzyme ADH. In excess, it will lead to the accumulation of acetaldehyde, a toxic substance that is also carcinogenic, because ADH works faster than ALDH. In alcohol intoxication, ethanol causes inebriation because of its effects on various areas of the brain causing physical and mental impairments in a progressive order as the person’s alcohol level increases (the person becomes more and more intoxicated), also known as the “flush syndrome”. Contrary to popular opinion, alcohol is not a stimulant, but rather the opposite. It is a depressant that to mimic GABA’s effect in the brain, binding to GABA receptors and inhibiting neuronal signaling, increasing the effect of the body’s naturally-occurring GABA. Alcohol acts primarily at the GABA receptor facilitate its action, thus in essence creating enhanced inhibition. This explains how alcohol depresses both a person's mental and physical activities. Furthermore, glutamate, the major excitatory NTA in the brain is inhibited by alcohol by inhibiting a subset of glutamate receptors (N-methyl-D-aspartate or NMDA) which diminishes the excitatory actions of glutamate and further promotes its depressive effects in the body. WERNICKE-KORSAKOFF ENCEPHALOPATHY Also known as Wernicke-Korsakoff Syndrome, this is an acute vitamin-deficiency related neurologic disorder that is commonly associated with chronic alcoholism. Thiamine (Vitamin B1), a coenzyme which plays a central role in cerebral metabolism, is deficient in Wernicke’s, thereby causing the so-called “Wernicke

triad”: Altered mental status, ataxic gait, and ophthalmoplegia and other neuropsychiatric symptoms. Wernicke-Korsakoff Syndrome is often associated, not only with chronic alcoholism, but also the subsequent thiamine deficiency resulting from it. One effect of high alcohol intake is a decrease in thiamine uptake by the gastrointestinal tract. Normally, thiamine uptake is via passive transport at high concentrations as with additional thiamine administrations. At low concentrations, as what is normally found in the body, it is by active transport. In the presence of a high alcohol environment in the gastrointestinal tract, thiamine uptake at low concentrations is inhibited. This often results in thiamine deficiency. HYPOXIA The main pathway of alcohol metabolism, which involves ADH and ALDH, results in the generation of NADH. The NADH then is oxidized by utilizing the ETC in the mitochondria, resulting in the transfer of electrons to molecular oxygen (O2), which then binds protons (H+) to generate water. To have enough oxygen available to accept the electrons, the hepatocytes must take up more oxygen than normal from the blood. Consistent with this assumption, studies have shown that ethanol metabolism tends to increase the hepatocytes’ oxygen uptake from the blood If the hepatocytes that are located close to the artery supplying oxygen-rich blood to the liver take up more than their normal share of oxygen, however, not enough oxygen may be left in the blood to adequately supply other liver regions with oxygen. ALCOHOLIC JAUNDICE Alcoholic jaundice signifies the progression of alcoholic liver disease (ALD). Alcoholic liver disease is a result of over consuming alcohol that damages the liver leading to a buildup of fats, inflammation, and scarring. Less common signs include skin conditions such as itchiness, eczema and psoriasis, bad reactions to medication such as antibiotic or pain relievers, frequent heartburn, and acid reflux. ALD can be fatal and its prevalence is influenced by factors such as genetics

which upon binding LPS to the endotoxin receptor CD14 activate the MyD88- independent signaling pathway through TLR4 , with consecutive production of proinflammatory cytokines such as tumor necrosis that contribute to hepatocellular damage. Cytokines and chemokines will be recruited contributing to inflammation and fibrotic repair processes. FIBROSIS This resembles the process of excessive wound healing as a result of increased fibrogenesis and decreased fibrolysis. In progressive fibrosis, liver parenchyma is replaced by excess ECM produced by activated hepatic stellate cells and myofibroblasts resulting in a distorted liver architecture and progressive functional impairment. In ALS, HSCs and MFBs can be stimulated by acetaldehyde, ROS, leptin, endocannabinoids and lipid peroxides. CIRRHOSIS This occurs when the liver has been inflamed for a long time, leading to scarring and loss of function. This can be a life-threatening condition. A complication of ALD Is hepatocellular carcinoma. An important trigger of tumor development is acetalydehyde, which is not only a toxin but also a highly reactive mutagen that forms stable DNA adducts, causes point mutation, sister chromatid exchanges, inhibits DNA repair, and via induces CYP2E1, activates pro-carcinogens to carcinogens. TREATMENT AND MANAGEMENT The first step in treating any level of alcoholic liver disease focuses on removing alcohol from the diet or abstinence. Once a person is diagnosed with alcoholic liver disease at any stage, it is recommended to never resume drinking. Any conditions that have reversed will typically return once drinking restarts. As alcohol dependency can make it more difficult to quit drinking alcohol, it is necessary to gradually reduce alcohol intake. Next is lifestyle change, wherein weight loss and abstinence from smoking might also be recommended since being overweight and smoking have both demonstrated a role in making alcoholic liver disease worse. Taking a daily

multivitamin is usually recommended as well. Third is medications, corticosteroids or pentoxifylline may be used for reducing inflammation in people with acute alcoholic hepatitis while they are being treated in a hospital. Other medications that show potential for treatment and are currently being studied include: (1) probiotics and antibiotics (2)stem cell therapy (3)medicines that target the inflammation pathway. Lastly, liver transplant which is the last resort. This can be an outcome of advanced-stage liver disease and often means that a liver transplant is the only option for prolonged survival. Typically, only people who can show at least six months of abstinence from alcohol before the procedure and those with other organ systems that are healthy enough to undergo surgery will be considered for transplant.