MCP 4

Question 1

MEOS

Answer 1

microsomal alcohol oxidizing system. made of cyt P450 enzymes, mainly CYP2E1. converts ethanol to acetaldehyde using NADPH as an additional electron donor and O2 as an electron acceptor.

Question 2

ADH isozymes

Answer 2

ADH1: present in high levels in liver and has highest affinity for alcohol
ADH2: found in liver and lower GI tract
ADH3: found in many tissues, inactive toward ethanol, but active towards long chain alcohols
ADH4: present in upper GI tract. At high ethanol concentration in upper GI, the conversion of ethanol is done by ADH4 and can contribute to cancer risk

Question 3

acetaldehyde dehydrogenase

Answer 3

ALDH. catalyze oxidation of acetaldehyde to acetate with generation of NADH. 80% done by ALDH2 in mitochondria, the rest done by ALDH1 in cytoplasm. inactive ALDH2 leads to nausea, vomiting, and ALDH inhibitors can be used to treat alcoholics

Question 4

acetyl CoA synthetase

Answer 4

acetate to acetyl CoA. ACS 1 is primary isoform in liver. Cytosolic enzyme that generates acetyl CoA for the pathways of cholesterol and fatty acid synth. Pathways regulated by cholesterol and insulin. ACS II is used by other tissues, and is in the mitochondria. Acetyl CoA generated by ACS II can enter the TCA cycle

Question 5

cytochrome P450

Answer 5

2 major catalytic components: cytochrome p450 reductase which transfers electrons from NADPH, and cytochrome p450 which contains binding sites for O2 and substrates and carries out the reaction

Question 6

CYP2E1

Answer 6

highest activity when ethanol is substrate. Part of the MEOS pathway. has a higher Km for ethanol than ADH1 so becomes more involved when large quantities of alcohol are consumed. Yields acetaldehyde and ROS, resulting in oxidative stress and cell damage. Chronic consumption of alcohol induces large amounts of CYP2E1 production. it increases ethanol clearnance but makes acetaldehyde too fast for the body to handle it

Question 7

Variations in ethanol metabolism

Answer 7

depends on genotypes, drinking history, gender, and average amounts of ethanol an individual consumes

Question 8

acute effects on lipid metabolism in liver

Answer 8

inhibition of fatty acid oxidation and stimulation of TAG synth leading to fatty liver and ketoacidosis or lactic acidosis, causing hypo or hyperglycemia. effects are reversible. Acute effects are the result of increased NADH/NAD+ ratio

Question 9

mech of acute effects on lipid metabolism in liver

Answer 9

1. ethanol oxidation increased NADH/NAD+ ratio
2. high ratio inhibits fatty acid oxidation and TCA cycle, accumulating fatty acids
3. fatty acids are reesterified to glycerol 3-P by acyltransferases. TAGs are converted to VLDL in which accumulate in liver and leak to blood leading to fatty liver and ethanol induced lipidemia
4. fatty acids that get oxidized to acetyl CoA then to ketone bodies. high NADH/NAD+ ratio inhibits TCA cycle
5. Leads to ketoacidosis
6. High NADH/NAD+ ratio leads to increased lactate production and lactic acidosis
7. increase in blood lactate decreases uric acid excretion by kidney, hence why people with gout shouldnt drink
8. Increased NADH/NAD+ shifts lactate equilibrium toward production of lactate at expense of pyruvate. Pytuvate formed cannot enter gluconeogenesis, which is why drinking can lead to hypoglycemia in a fasting state. Drinking with a meal can cause hyperglycemia because high ratio inhibits glycolysis @ glyceraldehyde 3-P dehydrog step

Question 10

effects of chronic alcohol consumption

Answer 10

1. adduct formation with amino acids causes a decrease in protein synth.
2. accumulation of prots causes water to enter into hepatocytes with swelling of liver, leading to portal hypertension and hepatic architecture disruption. cell damage leads to release of hepatic enzymes like ALT and AST.
3. acetaldehyde forms adduct with GSH and antioxidant enzymes so they cant fight against ROS
4. MEOS increases ROS production, lipid peroxidation, and cell damage.
5. peroxidation of lipids inhibits electron transport and stops acetaldehyde to acetate conversion
6. adduct formation with prots can cause loss of function. formation with tubulin causes decreased secretion of plasma prots and VLDL from liver. prots accumulate in liver

Question 11

hepatic cirrhosis

Answer 11

irreversible liver damage. initially liver is enlarged, full of fat and crossed with collagen fibers (fibrosis) and has nodules of ballooning hepatocytes between fibers. as liver function is lost, the liver becomes shrunken (laennec cirrhosis). leads to increased blood bilirubin and jaundice