Alcoholic Liver Disease and the co-triggering Role of MEOS with Its CYP 2E1 Catalytic Cycle and ROS
Archives of Gastroenterology Research
Alcohol or ethanol, as the correct chemical term, causes upon prolonged use in high amounts alcoholic liver disease (ALD), attributable to metabolic products and byproducts from enzymatic degradation of ethanol rather than to the relatively inert ethanol itself. The present review aimed to analyze mechanistic steps involved in ALD with a focus on molecular aspects related to the microsomal ethanol oxidizing system (MEOS), cytochrome P450 (CYP) 2E1, and ROS (reactive oxygen species). Apart from
... ecies). Apart from alcohol dehydrogenase (ADH), hepatic metabolism proceeds also via MEOS, which functions independently from ADH and catalase. MEOS is dependent upon various CYP isoforms with a preference of the CYP 2E1 isoform and requires not only NADPH + H + as cofactor but also molecular oxygen. During alcohol metabolism via MEOS and CYP 2E1, and due to incomplete split of oxygen within the catalytic CYP 2E1 cycle, reactive oxygen species (ROS) are generated as toxic byproducts such as ethoxy radical CH 3 CH 2 O•, hydroxyethyl radical CH 3 C(•)HOH, acetyl radical CH 3 CHO•, single radical 1 O 2 , superoxide radical HO• 2 , hydrogen peroxide H 2 O 2 , hydroxyl radical HO•, alkoxyl radical RO•, and peroxyl radical ROO•. Under mechanistic aspects, convincing evidence suggests that microsomal oxidative stress by radicals generated in liver microsomes through CYP 2E1 is directly involved in triggering early stages of ALD such as alcoholic fatty liver disease. Microsomal oxidative stress is also indirectly responsible for late stages of ALD such as liver cirrhosis, likely via modification of the immune system. In addition, radicals are generated by CYP 2E1 also in liver mitochondria causing mitochondrial oxidative stress and in the mucosa of the intestinal tract, suggesting some cotriggering pathogenetic role especially via endotoxins derived from the gut microbiome. In conclusion, MEOS, CYP 2E1, and ROS are primarily involved in triggering ALD via radical based toxic effects and alterations of the immune system.