Presence of Nonoxidative Ethanol Metabolism in Human Organs Commonly Damaged by Ethanol Abuse

Abstract

Acetaldehyde, the end product of oxidative ethanol metabolism, contributes to alcohol-induced disease in the liver, but cannot account for damage in organs such as the pancreas, heart, or brain, where oxidative metabolism is minimal or absent; nor can it account for the varied patterns of organ damage found in chronic alcoholics. Thus other biochemical mediators may be important in the pathogenesis of alcohol-induced organ damage. Many human organs were found to metabolize ethanol through a recently described nonoxidative pathway to form fatty acid ethyl esters. Organs lacking oxidative alcohol metabolism yet frequently damaged by ethanol abuse have high fatty acid ethyl ester synthetic activities and show substantial transient accumulations of fatty acid ethyl esters. Thus nonoxidative ethanol metabolism in addition to the oxidative pathway may be important in the pathophysiology of ethanol-induced disease in humans.

Stimulation of synaptosomal free radical production by fatty acids: Relation to esterification and to degree of unsaturation

“…Concentrations of 25 tiM of ethylated fatty acids have been reported for cerebral cortex of acutely intoxicated humans, the bulk of these being derived from unsaturated fatty acids [3]. The concentrations of fatty acid esters used in the present study are thus physiologically relevant.…”

“…This non-oxidative pathway of ethanol metabolism has been found to be present to a varying degree in a large range of tissues derived from both human and animal studies, and has been proposed to be important in the pathophysiology of ethanol-induced damage [2]. The formation of fatty acid ethyl esters after ethanol consumption occurs predominantly in the pancreas and liver, but also within the brain [3]. These esters have been proposed to produce neurological damage perhaps by causing both membrane disordering and disruption of mitochondrial function [4], and their accumulation may be a factor in the pathogenesis of fetal alcohol syndrome [5].…”

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

“…20 Although adipose tissue and pancreas of these individuals had the highest levels of FAEEs, none of them had pancreatitis. Ethyl oleate was reported to be the most abundant FAEE in pancreata of humans and rodents exposed to ethanol.…”

“…To determine the relative toxicities of FAEEs and the parent NEFAs, 300 mmol/L of the most prevalent NEFAs in the human pancreatic necrosis collections 11,20,32 were added at relevant concentrations to acinar cells, and LDH leakage was measured over 4 hours ( Figure 1A). These NEFA concentrations used are within the range of those noted in human pancreatic necrosis collections.…”

“…Uncontrolled release of lipases into fat, whether in the pancreas or in the peritoneal cavity, may result in fat necrosis, UFA generation, which has been associated with SAP. 11,12 Pancreatic homogenates were also noted to have an ability to synthesize FAEEs from FAs and ethanol,20,23 and the putative enzyme for this was thought to be a lipase. 24,25 It has been shown that the FAEE synthase activity of the putative enzyme exceeds its lipolytic capacity by several fold.…”