Major Mechanisms In Alcohol Induced Liver Injury Biology Essay

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Since the beginning of recorded medical history, the organ-damaging effects due to the consumption of alcohol have been known. Its negative effects are linked to numerous pathologies such as neurotoxicity, cardiomyopathy (heart disease), fetal alcohol syndrome, cancer, and liver injury (Zima, et al., 2005). It is widely accepted that most tissues of the body contain enzymes capable of alcohol metabolism, but significant metabolic activity only occurs in the liver and, to a lesser extent, the stomach (Lieber, 2005). It is also believed that only 10% of the alcohol consumed is eliminated by the kidneys and lungs, leaving the liver to oxidize the remaining 90% (Lieber, 2005). Since the liver is so important in ethanol digestion, it is thought to be the most harmed organ by ethanol consumption. Because of its important role in this type of metabolism, and since it drastically suffers alcohol's effects, the major pathway on what causes this damage will be the topic of focus.

The liver has a wide range of functions, including detoxification of the blood, protein synthesis, fat storage, and production of chemicals used in digestion (Dey, et al., 2006). While the mechanisms for alcohol metabolism within the liver are not fully understood, several enzymatic pathways have been commonly accepted among the medical community. The major pathway for ethanol disposition involves alcohol dehydrogenase (ADH), an enzyme (found mainly in the liver) that catalyzes the conversion of ethanol to acetaldehyde (Lieber, 2005). In ADH-mediated oxidation of ethanol, hydrogen is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD) as a result of acetaldehyde production. This NAD is then converted to its reduced form, NADH, consequentially producing an excess of reducing equivalents in the liver (Lieber, 2005).

This lowered NAD/NADH ratio is thought to have many hepatoxic (chemically-driven liver damaging) effects (Lieber, 2005). While the reasons as to why these reducing equivalents are so harmful are not fully understood, it is generally supported that increased NADH levels depress the citric acid cycle occurring in the liver cells' mitochondria because of a slowing of the reactions of the cycle that depend on the NAD/NADH ratio. This results in decreased ATP production and cell damage (Lieber, 2005). In addition, the mitochondria will use the hydrogen equivalents originating from ethanol, rather than those derived from the oxidation of fatty acids that normally serve as the main energy source of the liver. This, in turn, leads to hepatic fat accumulation within the liver which will likely decrease the organ's function. Amplified NADH levels have also been observed to raise the concentration of α-glycerophosphate, which are thought to favour hepatic triglyceride accumulation by trapping fatty acids which would, again, cause inhibitory effects against the liver (Lieber, 2005).

However, these damaging effects of NADH accumulation are not the only negative consequences of alcohol metabolism by ADH. All of the known pathways of ethanol oxidation result in oxidative stress and associated lipid peroxidation (oxidative degredation of lipids), either directly or through the product acetaldehyde (Cahill, 2005). This acetaldehyde, which is a type of reactive oxygen species (ROS), is recognized for having numerous harmful effects in the liver. Several major effects of acetaldehyde include damage to mitochondrial DNA (although the mechanism of this damage is unknown) and an influence on apoptosis, where the ROS increases the mitochondria's permeability by opening pores and allowing an influx of the apoptosis-promoting proteins p53 and Bax (Cahill, 2002). Acetaldehyde is also believed to be toxic to liver cells by increasing antibody production, inactivating enzymes, and depressing DNA repair mechanisms (Lieber, 2005).

This acetaldehyde product may also have important secondary implications. Some evidence indicates that this compound tends to bind with a tripeptide known as glutathione (GSH) which helps prevent oxidation of important cell complexes by being oxidized itself. This, in turn, inhibits GSH's ability to serve as a cofactor for glutathione transferase, which helps remove certain drugs and chemicals as well as other reactive molecules from the cells (Cederbaum, et al., 2009). It has also been observed that this binding results in increased GSH loss from liver tissue and, as expected, increased oxidative degradation of lipids (Lieber, 2005).

While the outlined pathway of alcohol metabolism by ADH is only one of many ways the liver processes ethanol, similar treatments for the resulting liver damage can be applied to the vast majority of physiological damage. The most obvious way to counteract alcohol's harmful effects is through reduction of alcohol consumption, where the detrimental substance is directly reduced, allowing the body (namely, the liver tissue) to naturally heal and to restore its natural fat composition. If more rapid treatment is required, administration of antioxidants or GSH-replenishing agents can prevent or reduce the toxic actions of alcohol (Dey, et al., 2006).

These treatments, along with the ADH pathway are only a small fraction of the aspects involved in alcohol-induced liver damage. With numerous additional enzymatic pathways known, in addition to the consistent discovery of new alcohol metabolism mechanisms in humans, new, more effective treatments for this liver damage will likely arise. Reactive oxygen species were the topic of focus, but one who is looking further into liver damage should also consider the effects of another known group of damaging compounds known as reactive nitrogen species. Additional questions should be asked by considering what other tissues are affected by alcohol consumption, and what different enzymes are involved.

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