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Josh 11-14-2012 01:16 AM

Alcohol and Apoptosis?
Is alcohol related to apoptosis and how?

Zagami 11-15-2012 10:19 AM

Re: Alcohol and Apoptosis?
Whole body is damaged by alcohol (ethanol) abuse but those more involved are liver, brain, heart, bone. The mechanisms by which ethanol determine tissue damage is always same, with small variations in the pathway. For to understand the way which ethanol acts on the involved cell, we will report the pathophysiological conditions that occur in the liver. Alcohol is metabolized in the liver cells by two enzymes, alcohol dehydrogenase (ALD) and, particularly after chronic alcohol consumption, cytochrome P450 2E1 (CYP2E1). Both enzymes convert alcohol to acetaldehyde, a toxic substance. Some of the acetaldehyde interacts with proteins in the cells, forming compounds called adducts that can activate certain immune cells to produce various cytokines, including interleukins (ILs), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α). Specific binding by TNF-alpha leads to activation of caspase 8 (key component of ethanol-induced apoptosis) from procaspase 8, which in turn activates caspase 3. In addition to acetaldehyde, alcohol metabolism by CYP2E1 also generates highly reactive molecules known as reactive oxygen species (ROS), which accumulate primarily in mitochondria. ROS normally are eliminated from the cells by antioxidants, especially glutathione (GSH). Alcohol, however, depletes the cell’s GSH stores, thereby further exacerbating ROS accumulation in the mitochondria. This process leads to the release of cytochrome c from the mitochondria. When cytochrome c is released from mitochondria it forms a complex with procaspase 9 and its cofactor apoptotic protease-activating factor 1 producing an active “apoptosome”. The apoptosome, promote production of IL-8, and activates caspase 3, and execution of the apoptotic program follows that leads at DNA fragmentation. Finally, alcohol leads to increased levels of a bacterial protein called endotoxin in the blood and in the liver, which activates the Kupffer cells. These cells then produce TNF-α, which in turn activates the stellate cells, to produce transforming growth factor beta (TGF-) and collagen. TNF-α production also leads to increased production of chemokines (e.g., IL-8), which attract inflammatory cells from the bloodstream to the liver, contributing to liver inflammation. Excess TNF-α and chemokines production also causes increased production of adhesion molecules that play an important role in fibrosis. Thus, all of these diverse pathways contribute to inflammatory reactions and fibrosis and culminate in the induction of apoptosis and organ damage.

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