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The role of nad/nadh in neurodegenerative diseases and addiction.

Over the centuries, alcohol has been one of the favorite mood-altering drugs worldwide. Alcohol is used by millions of people, despite its adverse effects. After administration, alcohol is readily absorbed in the gastrointestinal tract, and the hepatic elimination process requires oxidation. Alcohol consumption is linked with malnutrition and increased energy requirements. Alcohol-induced inflammatory reactions in vital organs lead to impaired food absorption and digestion. Acetaldehyde, the end product of alcohol metabolism, can prevent activation of vitamins. (1)

Biochemistry and Pathophysiology of Alcohol Metabolism After administration, alcohol (ethanol) is metabolized to acetaldehyde by the enzymatic action of alcohol dehydrogenase with NAD+ as a coenzyme. Acetaldehyde is then oxidized to acetic acid, 002. and water through the tricarboxylic acid (TCA) cycle. The adverse events of alcohol are directly associated with increased production of acetaldehyde and NADH.

CH3CH2OH + NAD CH3CH = 0 + NADH + H'

In the first step, aldehyde dehydrogenase (ALDH), cytochrome P450 (CYP2E1), alcohol dehydrogenase (ADH), and catalase are involved in metabolic elimination of alcohol. Genetic differences in expression of these enzymes lead to alcohol-related disorders/disease and addictive behaviours.

Alcohol metabolism leads to hepatic oxygen deficits, adducts and ROS formation, and interaction between alcohol metabolites. These pathophysiological changes lead to changes in cell's redox states: that is, altered ratio of NADH to NAD+, impaired metabolism, tissue damage, and so on. (2)

Several physiological processes require NADH, including conversion of pyruvate to lactate, synthesis of lipids, and the electron transport chain. Among alcoholics, pyruvate is converted into lactic acid that results in lactic acidosis, reduced energy synthesis. and hypoglycemia. Excessive formation of NADH causes biochemical anomalies, including defective lipid biosynthesis. NADH is used as a reducing agent for glycerol and fatty acid synthesis. Most heavy drinkers are obese due to these pathophysiological changes. (3) Excessive NADH is utilized in ETC to synthesize ATP. This reaction curtails normal fatty acid oxidation and the TCA cycle. This results in accumulation of acetyl-CoA or fats with net production of ketone bodies. Increased fat synthesis leads to hepatic deposition and release into the bloodstream that causes CVD disorders. (4-6)

Hepatic Metabolism of Alcohol

Acetaldehyde is the key toxic substance in alcohol metabolism. In large amounts, acetaldehyde is not converted into acetic acid and enters the bloodstream. Accumulated acetaldehyde can cause mitochondrial toxicity and hepatotoxicity including hepatitis and cirrhosis. (7)

Research studies have confirmed that acetaldehyde is the main cause of alcohol addiction. Accumulation of acetaldehyde in the brain inhibits neural-directed, enzymatic conversion of aldehydes to acids. These neurotransmitters in turn react with acetaldehyde to form morphine-like compounds and cause addiction. (8-10)

The deleterious effects of alcohol depend on blood alcohol concentration (BAC) and duration. After ingestion, alcohol is readily absorbed from the small intestine into the portal vein in the liver. In liver cells, alcohol is metabolized by several enzymes. The duration and extent of alcohol metabolism is termed as first-pass metabolism (FPM) (11,12)

BAC is influenced by several other factors, including food intake, digestion, type of alcohol, genetics. and smoking. Elimination of alcohol is influenced by duration of alcohol consumption, age, diet, and time of day. (13-15) Alcohol metabolism causes altered redox state in liver cells with formation of ROS. (16-19)

Metabolic Pathways of Alcohol and Redox Reaction

Apart from the liver, gastric ADH also contributes to FPM. The predominant site of FPM is, however, controversial.(11,20,21) Some studies have suggested that the main site of FPM is the liver. (12)

Alcohol is also metabolized in extrahepatic tissues that lack ADH. Brain cells contain catalase and CYP450 enzymes that facilitate alcohol metabolism. Generally, alcohol is metabolized via oxidative and nonoxidative pathways. The oxidative pathways involve 0YP450 2E1, catalase, and ADH. (18,22)

Cytosolic ADH converts alcohol to acetaldehyde. The reaction involves nicotinamide adenine dinucleotide (NAD) and intermediate carrier of electrons which is then reduced to two electrons and NADH. Peroxisomal catalase requires hydrogen peroxide to oxidize alcohol. In elevated alcohol concentrations, microsomal CYP2E1 converts ethanol to acetaldehyde, which is then converted to acetate by ALDH2 with NADH and ROS. Increased formation of ROS can cause oxidative stress and induce mitochondrial derangement and toxicity.(23-25)

ADH

Oxidative metabolism of alcohol involves hepatic ADH that yields acetaldehyde, a toxic metabolite and addictive-behavior mediator. The ADH enzyme family comprises five enzymes with unique kinetic and structural properties. At higher alcohol concentrations, alcohol is eliminated at a higher rate due to presence of enzymes with higher Km values. (28) The enzymatic oxidation yields two electrons to form NADH. This results in a highly reduced hepatic cytosol environment and leaves the liver cells vulnerable to ROS and acetaldehyde-mediated damage. Oxidative Metabolites of Alcohol

Oxidative metabolites of alcohol, including acetaldehyde and acetate, induce cellular damage via several pathophysiological mechanisms.

Acetaldehyde is metabolized to acetate by the enzymatic action of ALDH2 in mitochondria. This leads to formation of acetate and NADH, which are then oxidized by the mitochondrial electron transport chain. (27) Acetaldehyde binds to microsomal enzymes, proteins, and microtubules to form adducts. These adducts react with brain dopamine to form salsolinol, a chief chemical involved in the alcohol dependence mechanism. Adducts react with cellular DNA to form carcinogenic DNA adducts, including [N.sup.2]-propanodeoxyguanosine. This results in impaired protein secretion in the liver to cause hepatomegaly. (28) Similarly, acetate is metabolized to acetyl CoA and cholesterol via the cholesterol biosynthetic pathway.

NAD and NADH in Addiction

Alcohol metabolism induces changes in the cellular redox state: that is, the ratio of NADH to NAD+ contributes to several disease processes.

The generation of NADH via the oxidation of alcohol and mitochondrial ETC results in the net transfer of electrons to molecular oxygen. 02 binds with H+ to form H20. To accept more electrons, the liver cells must gain more oxygen from blood circulation. (29) Inadequate oxygen or increased biological oxygen demand leads to hypoxia in liver cells. Chronic alcoholism is linked with hypoxia in hepatocytes, particularly the perivenous hepatocytes. (3,30) In addition to hepatocytic hypoxia, ethanol indirectly increases oxygen utility by activation of hepatic Kupffer cells. Activated hepatic macrophages release stimulatory molecules, including PGE2, which promotes metabolic processes that require oxygen molecules and cause hypoxia.

NADH oxidation by ETC-and CYP2E1-mediated ethanol metabolism generates ROS that induce lipid peroxidation and forms 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA). The metabolites can bind with proteins to form stable adducts called MDA--acetaldehyde--protein adduct. (31,32)

The rate of acetaldehyde and alcohol oxidation by enzymes is determined by the rate of NADH generation via mitochondrial ETC. The latter reaction requires oxygen and generates ATP. The oxidation of NADH depends on cellular oxygen supply and ATP requirements. In the limited state, ETC rate is reduced and impairs metabolism of ethanol and acetaldehyde. In addition, these changes may divert electrons to mitochondrial electron transport chain to form superoxides or ROS. (33)

Altered NADH/NA[D.sup.+] Levels and Gene Activation

Several cellular, biochemical reactions require NADH and NAD+ and respective ratio. Fluctuated ratio is often associated with defective alcohol metabolism as a result of increased hepatic NAD+/NADH ratio in mitochondria and cytoso1. (34.35) In cytosol. ADH-mediated metabolism of alcohol to acetaldehyde generates reducing equivalents, NADH. These molecules are then transported into the mitochondria by the malate-aspartate shuttle. In the mitochondria, NADH is predominantly produced by the enzymatic action of ALDH. These reactions result in increased availability of NADH to mitochondrial ETC.

Altered NADH/NAD ratio can impair the expression of certain genes involved in calorie restriction and food intake. NA[D.sup+] levels are the key regulators of certain genes involved in calorie restriction. (36)

Inactivation of those genes causes age-related and degenerative disorders including diabetes, cancer, and CVD. (37) Increased alcohol metabolism can alter NADH/NA[D.sup.+] ratio, affect gene expression, and increase the risk of lifestyle-related disorders.

Proper Oxidization of NAD/NADH for Addiction

Recovery Modulating or correcting the oxidative status of NADH/NAD-can reverse the negative effects of alcoholism and the addiction status.

Preventing reduced formation of acetaldehyde by alcohol oxidation via the mitochondrial ALDH2, subsequent reactions of mitochondrial ETC and adduct formation can promote addiction recovery. Formation of alcohol adducts directs the dopamine to form salsolinol, a key metabolite associated with alcohol dependence. This results in altered NADH/NAD-ratio; increased NADH concentration induces fatty acid biosynthesis to form triglycerides. Elevated triglyceride biosynthesis leads to hepatic accumulation and cause fatty liver.

Altered redox system can increase amino acid metabolism and lactic acidosis, inhibits TCA cycle, increases insulin sensitivity, and impairs cortisol and glucose metabolism. '8 These factors increase the predisposition to addiction and/or delay addiction recovery in chronic addicts.

Impaired energy metabolism (NAD', NADH, and ATP biosynthesis) with oxidative stress is a major cause of addiction-induced health disorders. These anomalies can affect several metabolic pathways including tryptophan metabolism. Impaired tryptophan metabolism is generally linked with addictive behaviors and mood disorders.4).41 Treatment of impaired energy metabolism and tryptophan metabolic disorders can facilitate the addiction recovery among chronic alcohol abusers. (41-44)

Notes

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by Dalai Akoury, MD
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