Biochemical Aspects of the Hepatic Microsomal Ethanol-oxidizing System (MEOS): Resolved Initial Controversies and Updated Molecular Views

Abstract

The hepatic microsomal ethanol-oxidizing system (MEOS) was initially confronted with much uncertainty, skepticism, scientific antagonism, and heavy discussions. Viewed as scientific challenges, this stimulated further research, and led to its successful separation from both, alcohol dehydrogenase and catalase, and its reconstitution that allowed defining the individual components of MEOS: cytochrome P450 (CYP), reductase, and phospholipids. Subsequently, it was challenging to elucidate the molecular basis of the microsomal ethanol oxidation. Unlike a usual dehydrogenation or simple oxidation process, ethanol oxidation via MEOS proceeds via reactive intermediates, commonly known as reactive oxygen species (ROS) and generated by various microsomal CYP isoenzymes including CYP 2E1, all of which are established components of MEOS. Due to its radical scavenging properties, ethanol combines with a small fraction of hydroxyl radicals and undergoes oxidation while the remaining radicals attack phospholipids of liver cell membranes. Chronic alcohol use enhances MEOS activity by upregulating CYP 2E1 combined with ROS generation, and thereby increases the metabolism of ethanol to acetaldehyde, its first metabolite with a high hepatotoxic potential. Considering the involvement of various CYP isoenzymes as constituents, MEOS is now best defined as a multi-CYP isoenzyme system, participating in ethanol metabolism and responsible for the molecular-based alcoholic liver disease.

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support

“…Other potential biomarkers are closely related to the metabolism of ethanol via the microsomal ethanol-oxidizing system (MEOS) with CYP 2E1 as its major component and the associated production of acetaldehyde and ROS [117][118][119][125][126][127][128][129][130]. This explains why antibodies against acetaldehyde proteins are found in the serum of individuals with an alcohol abuse.…”

The Purinergic P2X7 Receptor-NLRP3 Inflammasome Pathway: A New Target in Alcoholic Liver Disease?

“…The massive ROS production linked to the increase in membrane fluidity accounts for the perverse effects of chronic alcohol consumption. It is now clear that the microsomal ethanol-oxidizing system (MEOS) is involved in Kupffer cell activation, highlighting a key step in the transition from alcoholic fatty liver to alcoholic steatohepatitis [ 21 , 22 , 23 ]. Key components of MEOS are several forms of cytochrome P450 (CYP), especially its CYP 2E1 isoform, the NADPH-dependent cytochrome P450 reductase, and phospholipids [ 21 ].…”

“…Key components of MEOS are several forms of cytochrome P450 (CYP), especially its CYP 2E1 isoform, the NADPH-dependent cytochrome P450 reductase, and phospholipids [ 21 ]. Due to its radical scavenging properties, ethanol combines with a small fraction of hydroxyl radicals and undergoes oxidation while the remaining radicals attack phospholipids of liver cell membranes [ 22 ]. Chronic alcohol consumption upregulates MEOS activity and CYP 2E1 gene expression, leading to increased rates of alcohol degradation to acetaldehyde via MEOS and high amounts of toxic radicals that partially escape the scavenging properties of ethanol and cause liver injury [ 21 ].…”

Alcoholic Liver Disease and the co-triggering Role of MEOS with Its CYP 2E1 Catalytic Cycle and ROS

“…Whereas alcohol metabolism via ADH produces reducing equivalents in form of reduced nicotinamide adenine dinucleotide NADH + H + by reduction of NAD + , MEOS consumes reducing equivalents in form of reduced nicotinamide adenine dinucleotide phosphate NADPH +H + with increasing demand due to enhanced MEOS activity under conditions of prolonged alcohol use and if alcohol concentrations are intermediate or high [22,23]. This synergistic process is facilitated by the nicotinamide nucleotide transhydrogenase (NNT), [17,29,30]. Although several sources are known, which provide or consume reducing equivalents, the best studied is the respective interconnected action of ADH and MEOS (Figure 2).…”