Lecture 51 Flashcards
Alcohol Metabolism and Metabolic Effects of Alcohol Excess
1
Q
ethanol as energy source
A
- ethanol is 4th major “nutient”
- provides “empty calories” -> but a LOT of them
- a “standard drink” has about 14 grams of ethanol -> ~100 kcal/drink (ONLY from the alcohol)
- ethanol is only alcohol that can be consumed without any immediate toxic effects
pg 1323
2
Q
liver role in ethanol metabolism
A
- ethanol = alcohol, broken down to NADH
- ethanol is a small molecule which is soluble in both organic solvents and water, can easily cross membranes
- ethanol enters liver hepatocytes from blood stream and is metabolized by 2 different systems in the liver
- 80-90% of ethanol broken down to acetaldehyde by alcohol dehydrogenase
pg 1324
3
Q
alcohol dehydrogenase (ADH)
A
- metabolizes 80-90% of the ethanol in liver cells (predominantly)
- rate-limiting step
- only limiting factor is availability of NAD+
- converts ethanol to acetaldehyde and produces NADH (electron transfer to transport to ETC)
pg 1325
4
Q
kinetics of ADH
A
- Km of liver ADH (ADH1) is nearly 1 mmol/L (46 mg/L) -> the enzyme is essentially saturated after only one drink -> with a second drink, ethanol remains in circulation because it takes time for it be released from ADH
- ethanol metabolism follows zero-order kinetics
- most people metabolize ~10 g of alcohol per hour, and the blood alcohol level decreases by about 0.15 g/L every hour
pg 1325
5
Q
genetics of ADH
A
- exists as a family of at least 6 isoenzymes with varying specificity for chain length of the alcohol substrate
- known polymorphism that reflects on individual experiences (aka different alcohol tolerance based on speed of metabolism)
pg 1325
6
Q
liver role in ethanol metabolism pt 2
A
other method of ethanol metabolism in the liver is MEOS (ER microsomal ethanol-oxidizing system) which is responsible for 10-20% of ethanol conversion to acetaldehyde
pg 1326
7
Q
ER microsomal ethanol-oxidizing system (MEOS)
A
- metabolizes only 10-20% in moderate drinking (Km for ethanol is much higher than ADH) → uses cytochrome p450 enzymes
- requires oxygen and NADPH (from PPP) for conversion to acetaldehyde
- induced at transcriptional, post-transcriptional, and post-translational level in heavy drinkers
- induction potentiates toxicity of acetaminophen
pg 1327
8
Q
liver role in ethanol metabolism pt 3
A
- ethanol can be converted to acetaldehyde by catalase in the brain -> accounts for less than 2% of metabolism
- catalase has no role in the liver and is rarely used
pg 1328
9
Q
acetaldehyde
A
- very toxic
- accounts for most of the physical damage in chronic alcohol use
- symptoms of acetaldehyde toxicity include flushing of the face and nausea
pg 1329
10
Q
chronic alcohol use and liver disease
A
developments of hepatic fibrosis: proposed model
- acetaldehyde contributes to chronic disease in alcohol use disorder
- acetaldehyde accumulation is toxic
- acetaldehyde activates Kupffer cells (resident macrophages)
- activated Kupffer cells release TGF-β which activates stellate cells (vitamin A)
- stimulated stellate cells produce ECM, collagen, metallo, and proteases -> this leads to fibrosis
- toxicity comes from acetaldehyde in chronic alcohol use
pg 1330, 1339
11
Q
liver role in ethanol metabolism pt 4
A
in mitochondria, acetaldehyde is broken down into acetate by ALDH
pg 1331
12
Q
aldehyde dehydrogenase (ALDH)
A
- two enzymes with different locations
- mitochondrial ALDH (ALDH2) -> high affinity and specificity
- cytosolic ALDH (ALDH1) -> may act on a variety of organic alcohols, toxins, and pollutants
- converts acetaldehyde to acetate
pg 1332
13
Q
ALDH genetics
A
- polymorphism in ALDH2 in 30-40% of East Asians having an atypical ALDH with a single amino acid substitution (Glu->Lys, dominant negative) -> inefficient ALDH function
- results in oriental flush response, with vasodilation, facial flushing, and tachycardia
- provides a natural “protection” from alcoholism
pg 1332
14
Q
ALDH inhibition
A
- disulfiram (antabuse) → inhibitor of ALDH to cause oriental flush response (unpleasant reaction leading to alcohol avoidance)
- results in acetaldehyde accumulation
pg 1332
15
Q
liver role in ethanol metabolism pt 6
A
acetate converted to acetyl CoA by acetyl CoA synthetase (requires ATP)
pg 1333
16
Q
acetyl CoA synthetase I (ACSI)
A
- a cytosolic enzyme that generates acetyl CoA for the cytosolic pathways of cholesterol and fatty acid synthesis
- acetate entry into these pathways is under the strict regulatory control by mechanisms involving cholesterol or insulin
- most of the acetate generated enters the blood
- converts acetate to acetyl CoA
pg 1334
17
Q
liver role in ethanol metabolism pt 7
A
- acetate can be released to blood to provide energy to muscles
- acetyl CoA converted to FAs and released in VLDL to the blood
- excess acetyl CoA converted to ketone bodies which are then released to the blood stream
pg 1335
18
Q
metabolic effects of acute alcohol use
A
- NO regulation for ethanol metabolism so NADH accumulates -> NADH allosteric regulator for many pathways leading to the following effects:
- hypoglycemia (in fasted state) -> liver cannot activate GNG (pyruvate to lactate uses NADH)
- transient hyperglycemia (in well-fed state)
- lactic acidosis
- hyperuricemia
- ketoacidosis
- hyperlipidemia
- fatty liver (ALD)
pg 1337-1338
19
Q
hepatic steatosis/fatty liver
A
- caused by aging, alcoholism, certain drugs, obesity, overnutrition (poor diet), and sedentary lifestyle
- reversible by lifestyle changes -> liver can go back to normal with proper changes
- MAFLD and AFLD are fatty liver (metabolic alcoholic fatty liver disease)
- a risk factor for: insulin resistance, diabetes, atherosclerosis, cardiovascular diseases
- in alcohol use disorder, steatosis/fatty liver leads to steatohepatitis and eventually cirrhosis (end stage liver disease)
pg 1340
20
Q
malnutrition in alcohol use disorder
A
- significant amount of the daily caloric intake comes from ethanol
- all negative effects on the liver, pancreas, and GI tract further increase nutritional malabsorption
- two vitamin deficiencies are particularly prevalent in patients with alcohol use disorder:
- folate deficiency is often seen, which results in megaloblastic anemia
- thiamine deficiency due to chronic alcohol use causes Wernicke-Korsakoff syndrome
pg 1341
21
Q
Wernicke’s encephalopathy
A
- symptoms: confusion, tremors, ataxia (loss of coordination), nystagmus, and other vision problems
- at this stage, the damage is not permanent and can be reversed by thiamine supplementation
- usually, in hospital admissions, thiamine is injected to assure delivery (the intestinal damage in alcoholics interferes with absorption)
- damage is largely reversible
pg 1342
22
Q
Korsakoff syndrome
A
- as the Wernicke’s stage progresses, eventually the symptoms of Korsakoff syndrome will develop
- this will include memory loss and inability to form new memories, confabulation, hallucinations, and delerium
- damage at this stage is usually irreversible and brain damage is permanent
pg 1342
23
Q
alcohol consumption and pregnancy
A
- during pregnancy, estrogen levels largely inhibit the activity of ADH
- alcohol in the blood of the mother moves to the blood of the fetus
- ability of the fetus to metabolize alcohol is suppressed (ADH is not expressed yet) (ADH detectable at 2 months gestation but only at 5-10% activity)
- alcohol remains longer in the blood and interferes with the ability of the fetus to use oxygen and develop normally
- exposure during the first trimester can be especially harmful
pg 1343
24
Q
fetal alcohol spectrum disorder (FASD)
A
- any physical or developmental disorders caused by prenatal alcohol exposure
- estimated to be 2-5% of population
- changes depend on the amount, frequency, and the timing of the consumption of alcohol by the mother during pregnancy
pg 1343
25
Q
methanol (CH3OH)
A
- formed in very small amounts during fermentation
- potential hazard in home distillation of alcohol
- metabolized in the liver by ADH and ALDH
- methanol -> formic acid -> formaldehyde
pg 1344
26
Q
ethylene glycol
A
- found in automotive antifreeze or radiator coolants
- colorless, odorless sweet liquid -> attractive for children
- metabolized in the liver by ADH and ALDH
- ethylene glycol -> glycol aldehyde -> glycolic acid
- VERY toxic
pg 1345
27
Q
treatment for methanol and ethylene glycol toxicity
A
- administration of antidotes
- fomepizole (IV) -> competitive inhibitor of the ADH enzyme (used in ER)
- ethanol -> competes with methanol/ethylene glycol for ADH; ADH has 100x greater affinity for ethanol so successfully blocks their breakdown into toxic compounds
pg 1346
