Display Settings:

Format

Send to:

Choose Destination

ethanol degradation II

This ethanol degradation pathway begins with conversion of ethanol to acetaldehyde by cytosolic alcohol dehydrogenase. The resulting acetaldehyde passes into the mitochondrial compartment where it is converted to acetate (by mitochondrial aldehyde dehydrogenase). Should acetate be activated to acetyl-CoA within the liver, it would not be oxidized by the Krebs cycle because of the prevailing high ratio of NADH + H / NAD+ within the liver mitochondrial matrix. Consequently, acetate leaves the mitochondrial compartment and the hepatocyte to be metabolised by extra-hepatic tissues . Extrahepatic tissues take up acetate where it is converted to acetyl-CoA . Four distinct human ethanol degradation pathways have been described - three oxidative pathways and one nonoxidative pathway. All oxidative pathways mediate the oxidation of ethanol to acetaldehye which is then oxidized to acetate for subsequent extra-hepatic activation to acetyl-CoA . Oxidative pathways are differentiated based on the enzyme/mechanism by which ethanol is oxidized to acetaldehyde. The present pathway utilizes cytoplasmic alcohol dehydrogenase with the other two oxidative pathways utilizing endoplasmic reticulum Microsomal Ethanol Oxidizing System (MEOS) and peroxisomal catalase, respectively. MEOS is also known as Cytochrome P450 2E1. The nonoxidative pathway is less well characterized but produces fatty acid ethyl esters (FAEEs) as primary end products . Oxidative and nonoxidative pathways have been demonstrated in a range of tissues including gastric, pancreatic, hepatic and lung. Inhibition of oxidative ethanol degradation pathways raises both hepatic and pancreatic FAEE levels demonstrating that oxidative and nonoxidative pathways are alternative metabolically linked pathways. Pancreatic ethanol metabolism occurs predominantly by the nonoxidative pathway but oxidative routes to acetaldehyde have also been demonstrated in the pancreas - the cytochrome P450 2E1 & alcohol dehydrogenase pathways . Ethanol metabolism occurs predominantly in the liver and the resulting oxidative metabolite acetaldehyde is thought to play a role in alcohol induced liver injury. Additionally, there is now solid evidence that FAEEs also play a role in alcoholic pancreatitis . Blood and organ levels of FAEEs are raised by ethanol consumption with the highest concentration observed in the pancreas. FAEE generation from ethanol is greater in the pancreas than in any other organ suggesting that the pancreatic pathway contributes to raised blood and organ FAEE levels . Under conditions of acute ethanol consumption, the majority of ethanol is degraded by the hepatic oxidative pathways predominantly the alcohol dehydrogenase mediated pathway. However, under conditions of chronic ethanol consumption, hepatic MEOS activity and nonoxidative pathways are induced and quantitatively make a greater contribution to ethanol catabolism. The stimulatory effect of ethanol on Cytochrome P450 2E1 levels results in increased oxygen consumption, production of excess free radicals and increased metabolism of ethanol, vitamin A and testosterone - the chronic effects of which contribute to depletion of antioxidative activity. Antioxidative deficiency (glutathione, vitamin E, phosphatidylcholine) and excess free radicals are believed to subsequently contribute to the progression of alcoholic liver disease . Polymorphic loci for genes encoding enzymes of ethanol degradation pathways have been identified and resulting variant isoenzymes characterized and found to exhibit distinct kinetic properties. Indeed, genetically determined differences in ethanol metabolism may, in part, account for the variability of individual susceptibility to the physical complications of alcohol abuse .

from BIOCYC source record: HUMAN_PWY66-21
Type: pathway
Taxonomic scope
:
organism-specific biosystem
Organism
:
Homo sapiens
BSID:
142309

Supplemental Content

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...