S78: Metabolic Consequences of Alcohol Metabolism!Learning Objectives 1) Learn the two major pathways of ethanol metabolism in humans and their relative contributions as a function of alcohol levels. 2) Understand the metabolic complications that arise from overconsumption of ethanol with regard to NADH overload. 3) Recognize the physiological roles of cytochrome P450s in ethanol and drug metabolism. 4) Appreciate the consequences of chronic alcoholism on nutrition w/regard to vitamin nutrition. 5) Realize that moderate alcohol consumption is associated with reduced mortality. 1) Learn the two major pathways of ethanol metabolism in humans and their relative contributions as a function of alcohol levels. - Introduction!- Dep. on amt and frequency of consumption, alcohol= a nutrient, a toxin, a psychoactive drug!- Alcohol = 2.5% of energy intake in US popn over 18, up to 50% in heavy drinkers!- 3rd leading preventable cause of death!- Alcoholic Liver Disease (ALD)!- common pathology from chronic alcohol overconsumption!- steatosis (fatty liver) --> alcoholic hepatitis --> cirrhosis!- risk for develping ALD increases a lot w/consumption greater than 40g/day in men and 20g/day in women!- Alcohol Metabolism!- Ethanol= small molecule, lipid and water soluble, readibly absorbed thru GI tract!- Most of ethanol metab. by LIVER thru 2 enzyme systems:!- Alcohol dehydrogenase/acetaldehyde dehydrogenase: major route after light/mod. Etoh consumption!- Microsomal ethanol oxidizing systems (MEOS): uses cytochrome P450 enzyme, inducible w/alcohol consumption, predominant at higher level of Etoh consumption!-5% is excreted in urine, 5% is exhaled!- Alcohol Dehydrogenase (ADH)!- a cytosolic enzyme, catalyzes oxidation of ethanol --> acetaldehyde!- multiple isoforms/variants of this enzyme --> diff. rates of Etoh metabolism in diff. people!- humans have 7 genes for ADHs, degree of expression of diff. isoforms could influence likelihood of Etoh dependence!- Etoh --(ADH)--> acetaldehyde --> increased NADH in cytosol --| inhibits glycolysis !- Acetaldehyde Dehydrogenase (ALDH)!- Most acetaldehyde formed --> oxidized in mitochondria --(ALDH)-> acetate - Cytosolic and mitochondrial forms of ALDH found in most caucasians, about half of E asians only have cytosolic enzyme!- Mitochondrial form oxidizes > 80% of acetaldehyde!- Rxn uses NAD+ e- acceptor --> NADH in mitochondria!- Acetaldehyde exerts toxic effects in liver and can enter blod and exert toxic effects in other tissues --> hangover symptoms!- Microsomal Ethanol Oxidizing System (MEOS) - Alcohol dehydrogenase has a low Km for Etoh, can become saturated in increased levels of Etoh consumption!- NADH accumulates in cytosol due to ADH --> rxn is slowed by lower amts of NAD+!- SO we have another route to metabolize ethanol= MEOS!- MEOS uses a cytochrome P450 to oxidize Etoh --> acetaldehyde, w/NADPH and Etoh= e- donors, O2 e- acceptor !- Most CP450s found in ER!- w/mod. Etoh consumption, this pathway only does 10-20% of Etoh metabolism!- Higher levels of Etoh consumption, MEOS does larger %!- Acetaldehyde formed by either pathway --> metabolized to acetate by acetaldehye dehydrogenase!- Fate of Acetate from Alcohol Metabolism - Can be converted to acetyl-CoA by acetyl Co synthetase --> further metabolized in TCA cycle!- Liver: high NADH/NAD+ ratio from Etoh oxidation --| TCA cycle!- SO much of acetate made in liver --> exported to other tissues --> oxidized for E (7kcal/g)!- In liver: Acetyl CoA= substrate for fatty acid synthesis and ketone body formation! 2) Understand the metabolic complications that arise from overconsumption of ethanol with regard to NADH overload. - See above and below 3) Recognize the physiological roles of cytochrome P450s in ethanol and drug metabolism. - Cytochrome P450s - superfam of > 50 enzymes that contain a specific heme and carry out oxidation rxns using O2 as e- receptor!- many are monoxygenases= they add 1 of 2 oxygen atoms to the substrate, the other O --> H20!- NADPH= donor of the 2e-'s req. for the rxn!- What CP450s are good for: - Metab. wide variety of lipophilic compouds of exo/endogenous origin!- Many are very specific for substrate, some are broad!- Endogenous substances: Ch, steroids, prostaglandins, fatty aicds!- forming steroid hormones, bile acids, leukotrienes, 1-hydroxy and 1,25-dihydroxy-vit D!- Series of oxidation rxns, use NADPH and O2 for each oxidation!- Oxidize wide range of exogenous compounds= xenobiotics that we injest!- made lipophilic compounds --> more soluble/easier to excrete!- incl. drug used for treatment!- natural variations in people in P450 enzymes --> influence how long a certain drug functions in that person!- sometimes, productions of CP450 oxidation rxn are more toxic than substate (ex. nicotine)!- ex. acetamenophen - overdose of acet. --> more calls to poison control centers in US than any other pharma substnace and is responsible for 35% of liver failure!- Induction of CP450's!- Many CP450s are inducible by their substrates --> provides a more effective means of disposing of the substrate!- Since they're often very broadly specific --> complications and drug/drug interactions!ex. Giving drug a induces a CP450 that also acts on drug B --> reducing its effectiveness!- CYP2E1 (cytochome that functions best w/Etoh) increases 5-10x w/chronic Etoh consumption, while other CP450s are induced 2-4x!- The cytochrome CYP2E1 that can convert acetaminophen --> toxic metabolite is the same enzyme that catalyzes alcohol oxidation in MEOS. SO high levels of Etoh consumption increase the potential for acetaminophen toxicity in the liver.!- Acetaldehyde Toxicity!- Acetaldehyde formed by both AD and MEOS pathways, only about 90% is metab. by ADH!- Acetaldhye= highly reactive, can form cov. adducts w/amino groups on proteins and impair function of the proteins (e.g. MT proteins--> lower albumin secretion by liver)!- Can react w/glutathione --> interfere w/its ability to limit ROS formation/damage!- Can leave the liver and be absorbed by other tissues!- Mutant for AD w/about 8% activity of the WT enzyme, common in people of asian descent!- people w/this --> facial flushing, light headed, palpitations, nausea, headache when they drink etoh!- drug disulfiram (antabuse)= an inhibitor of AD, used to treat alcoholism, sim. rxn to small amts of etoh in people w/mutant AD, long half life (effective for a week)!- Acute effects of Etoh from Elevated NADH/NAD+ ratio: Fatty Acid Metabolism - High
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