Alcohol and Toxicology (NUTR*4510) PDF

NUTR*4510 Toxicology, Nutrition & Food Unit 5: Alcohol and Nutritional Status Alcohol (i.e. ethanol) Pharmacology: - Absorption: Rapid due to its small structure and both lipid and water solubility - 20% in the stomach, 80% in the small intestine - Active agent: Ethanol, the parent compoun...

NUTR*4510 Toxicology, Nutrition & Food Unit 5: Alcohol and Nutritional Status Alcohol (i.e. ethanol) Pharmacology: - Absorption: Rapid due to its small structure and both lipid and water solubility - 20% in the stomach, 80% in the small intestine - Active agent: Ethanol, the parent compound (not a metabolite) - Mechanism of action: Depressed CNS function - Membrane effects: Alters synaptic membrane function - Other (indirect) effects: Promotes release of adenosine, an inhibitory neurotransmitter Toxicology: 1) Acute consumption: Blood alcohol (g / 100 mL) Clinical signs / symptoms 0.01 – 0.05 Nearly normal behaviour 0.03 – 0.12 Mild euphoria, loss of inhibitions, some (Legal driving limit is 0.08) sensimotor impairment Impaired judgement, perception, memory; 0.09 – 0.25 significant sensimotor impairment Confusion, staggering gait, impaired vision, 0.18 – 0.30 exaggerated emotions 0.25 – 0.40 Stupor, vomiting 0.35 – 0.50 Coma, death! 2) Chronic consumption: - Due to long-term exposure to acetaldehyde and ROS promote inflammation and scarring of tissues (mainly the liver) - Results in intestinal damage, cirrhosis, pancreatitis, and oral and liver cancers  Alcohol/Ethanol Metabolism (in the liver) ~80% via alcohol dehydrogenase 1) Moderate alcohol consumption ~20% via CYP2E1 Alcohol Acetaldehyde (Stable) dehydrogenase dehydrogenase Ethanol Acetaldehyde Acetic acid CH3-CH2OH 2e- CH3-COH 2e- CH3-COOH CoA NAD+ NADH NAD+ NADH ↓CNS function DNA, protein, lipid damage Acetyl-CoA - Alcohol dehydrogenase: - Expressed in the liver; cytosolic TCA cycle fat synthesis - Product (acetaldehyde) is reactive – damages DNA, protein, lipids - i.e., Acetaldehyde contributes to ethanol-induced tissue damage (i.e., cirrhosis) - Acetaldehyde dehydrogenase: - Expressed in the liver; mitochondrial enzyme - Promotes safe metabolism of acetaldehyde to stable product, acetic acid - Acetic acid converted to acetyl-CoA and used as substrate in tricarboxylic acid (TCA) cycle, lipid synthesis, acetylation, etc. ~40% via alcohol dehydrogenase 2) High and/or chronic alcohol consumption ~60% via CYP2E1 O2 CYP2E1 Ethanol Acetaldehyde CH3-CH2OH 2e- CH3-COH NADPH + H+ NADP+ ROS DNA, protein, lipid damage Examples of ROS ** NEED GSH Ethanol Metabolism Low to moderate alcohol consumption (ALDH) CYP2E1 Acetaldehyde Dehydrogenase 2 pathways exist for the metabolism of ethanol/alcohol in the body (outside of the brain) - Alcohol dehydrogenase - CYP2E1 - How much alcohol (parent compound) goes through these two pathways will depend upon: - how much alcohol you are exposed to (AMOUNT) - how frequently you are exposed to larger amounts of alcohol (PATTERN OF EXPOSURE, i.e. ACUTE vs. CHRONIC intakes) - SNPs in CYP2E1 and ADH RISK of DNA or cellular damage (in the liver or brain, but also other tissues) will depend on SNPs in - CYP2E1, ADH, ALDH  Alcohol/Ethanol Metabolism (in the BRAIN) MAIN enzyme in the brain = Catalase (60%) RESULT = altered and then depressed CNS function Contribution of the enzyme alcohol dehydrogenase (ADH) in the brain is variable Acetic Acid ADH = alcohol dehydrogenase ALDH = acetaldehyde dehydrogenase doi: 10.1007/978-94-007-5881-0_8  Liver, GIT, pancreas Global status report on alcohol and health, World Heath Organization, 2011. Retrieved from: https://www.who.int/substance_abuse/publications/global_alcohol_report/msbgsruprofiles.pdf  Hormesis (or Hormetic Effect) Hormetic Effect - Low dose of a stressor can produce a beneficial response, but at higher doses there are negative/harmful outcomes Xenobiotic dose or exposure increases as you move from left to right along the X axis → Increasing toxic or adverse effects Outcome Health 1 0 1000 Dose of Stressor (e.g., xenobiotic) Maximum No effect in arbitrary units beneficial effect https://roguehealthandfitness.com/hormesis-for-health- and-longevity-a-guide/  2006 Study refers to men and women…more appropriate terminology would be MALES and FEMALES No relationship Hormetic zone Comparison of Alcoholic Beverages “drinks” or SERVINGS Do not memorize – information provided to understand/contextualize intake recommendations Beverage % alcohol Size of Size of Grams of by volume drink drink (oz) alcohol (ml) Beer 5 341 12 13.4 (bottle) Beer (can) 5 355 12.5 14 Light 3.5 341 12 9.4 beer (bottle) Light 3.5 355 12.5 9.8 beer (can) Wine 12 142 5 13.4 12 142 6 16.1 Spirits 40 28.4 1 8.9 40 35.5 1.25 11.2 40 42.6 1.5 13.4 Average = 14g  Old Alcohol Guidelines vs New Alcohol Guidelines Current Old Recommendations Recommendations (2021) (2023) Drinks per Occasion Females – no more than 3 drinks Females & Males, no Males – no more than 4 more than 2 drinks drinks Drinks per Week Females – no more than Females – no more than 6 10 drinks/week drinks/week Males – no more than 15 Males – no more than 7 drinks/week drinks/week **Drinks = a standard drink serving  Alcohol and Cancer Males Females 14g = 1 serving/drink 50+g = >3.5 servings Males For interest only Females  Alcohol and Cancer Ethanol alone is not a strong carcinogen, but it increases the carcinogenicity of other xenobiotics by: - Promoting carcinogen absorption into tissues - Ethanol acts as a solvent - Changing the metabolism and tissue distribution of other X by stabilizing CYP2E1 and/or competing for CYP metabolism (if these X are metabolized by CYP2E1) - Causing cell injury, which promotes cell division and cell proliferation, making cells more vulnerable to mutation - Inhibiting DNA repair mechanisms - Altering the immune response to neoplasms (new and abnormal tissue growth) → as a result these cells are not recognized as “wrong” by immune system and not destroyed…this increases the chance that the abnormal tissue could continue to develop into a tumor - Promoting the development of nutrient deficiencies that favour carcinogenesis by: 1. Changing nutrient intake 2. Changing nutrient utilization / metabolism 3. Changing normal physiology and function See next page DNA damage, strand breaks, mutations, etc. Acetic Acid Impair DNA repair → can’t fix errors Alter DNA methylation patters changes gene expression DNA damage  Alcohol/Ethanol & Nutrient Deficiencies Favouring Carcinogenesis 1. Ethanol-Induced Changes in Nutrient Intake i. Effect on Energy Production - In most animals, food intake is regulated by total energy requirement - Gross energy of ethanol = 7 kcal / g (GE –DE = ME) - Heavy drinkers may derive half or more of their calories from ethanol; however, ethanol does not provide significant metabolizable energy at high intakes, in part because: a. Ethanol increases metabolic rate and heat production b. Ethanol-induced changes in small intestine physiology and function, leads to poor ethanol (and nutrient) absorption c. Ethanol metabolism by Alcohol Dehydrogenase (ADH) uses reducing equivalents (NAD+) instead of storing them ii. Effect on Food Choice - Moderate levels of ethanol act as a mood stimulant and can increase food intake - High levels of ethanol act as a depressant and decrease food intake - High cost of alcohol may decrease budget for healthy foods  Alcohol/Ethanol & Nutrient Deficiencies Favouring Carcinogenesis 2. Ethanol-Induced Changes in Nutrient Utilization / Metabolism - Ethanol has most direct effect on the organs involved in nutrient utilization / metabolism, e.g., small intestine and liver i. Effect on small intestine - Ethanol affects motility patterns → inhibits enteric nervous system from detecting undigested nutrients and suppresses the impeding waves in jejunum and increases diarrhea - -Consequence: - Prevents nutrients and digestive enzymes from mixing - Prevents digested products from circling around the villi for absorption → can lead to malabsorption or nutrient deficiencies over time - Decreases transit time in the colon → diarrhea ii. Effect on liver - Increases in retinyl esterase activity (discussed further on an upcoming slide) iii. Effect on pancreas - reduced function to secrete enzymes into the small intestine needed for a) lipid, and b) protein digestion (discussed further on an upcoming slide)  Alcohol/Ethanol & Nutrient Deficiencies Favouring Carcinogenesis 3. Ethanol-Induced Changes in Normal Physiology and Function i. Effect on small intestine (Nutrient Absorption Problem) - Exfoliation of villi tips → nutrient deficiencies, and bleeding - Even moderate alcohol consumption may lead to nutrient deficiencies via this mechanism Heavy No Moderate drinking Alcohol drinking “chronic” Full absorption Shortened villi Villi = stubs/nubs capability (decreased Malabsorption of nutrients Long villi absorptive Bleeding or ulceration of Intact functional surface area) the villi = further nutrient epithelial barrier Decreased losses absorption of Increased susceptibility nutrients to infection (via open Reduced cell ulcers in the epithelial turnover to repair barrier) Blood in abdominal cavity triggers evacuation  ii. Effect on the Pancreas - 50 – 60 % of individuals with alcohol use disorders experience pancreatitis, impairing its function to secrete enzymes into the small intestine needed for a) lipid, and b) protein digestion - In ADDITION - Changes in bile composition due to impaired liver function can further alter lipid digestion and movement of dietary lipophilic X in the body a. Effect on lipid digestion Immobility, pneumonia, Impaired lipid digestion Death? other complications Decreased absorption of Steatorrhea fat soluble vitamins, Hip fracture Loss of balance (Fat in feces) especially vitamin D Alcohol Poor calcium status Osteoporosis consumption Common in chronic b. Effect on protein digestion alcohol consumers Impaired protein digestion/absorption Cancer & Less conjugating Diarrhea tissue Death? agents for phase II damage metabolism of X Problems with nutrient absorption can decrease availability of SAA (needed for PAPS and GSH) Any micronutrient absorption can also be an issue (**impacts on X metabolic capacity)  iii. Effect on liver: Alcohol-Associated Liver Disease (ALD) - 3rd leading cause of death in 25 – 64-year-olds - Due to acetaldehyde and superoxide formation and accumulation in liver that causes liver damage over time - ~20% of heavy drinkers develop cirrhosis; females are more susceptible - Causes a progressive disruption in metabolism of all classes of nutrients, evident as early as the fatty liver stage ALD is a continuum: Glen et al., BMJ, 2016;354:i4428 1 Liver Steatosis 2 Non-alcoholic steatohepatitis (NASH) Fibrosis 3 Cirrhosis 4 1. Fatty liver (Liver Steatosis) → acetate converted to fatty acids, then poorly exported from the liver. Impaired assembly of VLDL particles → Fat/lipid accumulation 2. Hepatitis/ NASH → initial cell damage and inflammation 3. Fibrosis → scarring of the inflamed liver → “hardening” or fibrotic liver tissue developes 4. Cirrhosis → accumulation of scar tissue (fibrosis) and gradual liver cell death… ↑ damage to liver = ↓ in OVERALL liver function, can lead to Cancer  Vitamin A Metabolism Functionally important for vision, reproduction, epithelial cell differentiation and bone growth Dietary vitamin A and β-Carotene are lipophilic, absorbed & transported from intestine to the liver in chylomicrons e.g. retinyl palmitate (the ester of retinol + palmitic acid) → main storage form of vitamin A in the body (in the liver) Biologically active or relevant form of vitamin A Deficiency syndrome to identify low vitamin A status is reduced night vision (need functional rhodopsin)  Alcohol and Vitamin A Status - Dietary vitamin A (all sources) converted to retinyl palmitate (a retinyl ester) and packaged with dietary lipids into a chylomicron - Chylomicron remnant returns to the liver, delivering dietary vitamin A, which is stored as retinyl palmitate in the stellate cells of the liver - When vitamin A is needed retinly palmitate is converted to retinol by the enzyme Retinly esterase - Blood levels of Retinol (bound to RBP and PA in a protein complex) and maintained within a homeostatic concentration range….when retinol is delivered to other tissues of the body more retinol is released from the liver into the blood to maintain this concentration. The blood [Retinol- RBP-PA] is used to measure whole body vitamin A status, when this value drops it indicates deficiency BUT since it’s maintained within a set concentration range it will not drop until liver vitamin A stores are depleted (so there are limited warning signs that you’re vitamin A deficient until it’s too late and the body stores are almost gone!) (Storage of retinly palmitate) Stellate cell LIVER Chylomicron Hepatocyte Gene Expression remnant Retinyl palmitate 1 2.b. Retinyl esterase Alcohol dehydrogenase Alcohol Retinol Retinoic acid Retinol-binding 2.c. protein (RBP) CYP2E1 4-hydroxy-retinol Prealbumin (PA) (a.k.a. Transthyretin) PA-RBP-Retinol excreted Maintained blood concentration range  Alcohol and Vitamin A Status Mechanisms of ethanol-induced vitamin A deficiency: 1. Acute alcohol consumption - Increases retinyl esterase activity, therefore increasing the conversion of retinyl palmitate to retinol - Decreases retinyl palmitate stores in stellate cells, specialized (i.e. differentiated) fibroblasts in the liver - Transiently increases blood retinol levels: deceiving, since blood retinol levels are measured to determine vitamin A status… Mechanisms of ethanol-induced vitamin A deficiency: 2. Chronic alcohol consumption a. Increases retinyl esterase activity, therefore increasing the conversion of retinyl palmitate to retinol - Decreases retinyl palmitate stores in stellate cells - Transiently increases blood retinol levels (maintained within a homeostatic range, so there is an upper limit) b. Induces/increases alcohol dehydrogenase expression/activity: converts retinol to retinoic acid → effects gene expression - Retinoic acid promotes epithelial cell differentiation, but is short lived (short half-life, then degraded)…so more retinoic acid needs to be produced from retinol to support gene expression c. Stabilizes CYP2E1: converts retinol to 4-hydroxy-retinol for excretion (vitamin A is lost to the body while liver stores are being depleted)…this can lead to vitamin A deficiency!! 3. Eventual cirrhosis is associated with damage and loss of function of hepatocytes and stellate cells, and therefore, impaired vitamin A metabolism, storage, and regulation → Depleted vitamin A stores impair the ability to repair damaged Small intestine villi (retinoic acid is a stimuli for stem cell differentiation ) Vitamin A supplementation with chronic alcohol intake: DANGEROUS! - Limited # stellate cells is the liver try to proliferate to compensate for excess vitamin A from supplements but instead return to fibroblast-like behavior, promoting fibrosis