Lecture 31+32

Question 1

metabolism of drugs occur in the liver in two phases?

Answer 1

phase I: involves cytochrome P450

Phase II: makes the molecules more polar
some drugs dont need phase I

Question 2

Role of CYP3A4 and CYP2E1

Answer 2

CYP3A4 = acts on drugs

CYP2E1 = acts on ethanol metabolism

Question 3

examples of things that interfere with CYP activity

Answer 3

ethanol induces CYP2E1

grapefruit juice inhibits CYP3A4 in the intestinal epithelial cells

Question 4

Degradation of Acetaminophen

Answer 4

major pathway:
degrade into Acetaminophen glucuronate and/or Acetaminophen sulfate

minor pathway involves CYP2E1:
converted to NAPQI

Question 5

high alcohol intake on acetaminophen metabolism

Answer 5

high alcohol intake induces CYP2E1, thus more drug will be broken down by this minor pathway

this will lead to a high NAPQI level, which leads to hepatic damage

Question 6

Acetadote (N-acetyl cysteine)

Answer 6

A drug that can be injected to prevent haptic damage in those who consumed a high amount of acetaminophen

Question 7

metabolism of a low amount of ethanol

Answer 7

ethanol is converted to acetaldehyde by alcohol dehydrogenase (needs NAD)

acetaldehyde is taken to the mito where it is converted to acetate by acetaldehyde DH2 (uses NAD)

acetate is released into the blood

Question 8

what can happen to the acetate released into the blood?

Answer 8

the skeletal muscles and heart have an enzyme acetyl CoA synthetase which uses acetate for the TCA cycle

Question 9

MEOS in hepatocytes

Answer 9

bound to the ER membrane and uses ethanol and NADPH to form acetaldehyde

larger Km but lower affinity

has CYP2E1 and CYP3A4

chronic alcohol consumption induces MEOS

Question 10

Mitochondrial aldehyde DH-2 VS Cytosolic aldehyde DH-1

Answer 10

1:
has a low affinity
acts when cytosolic acetaldehyde accumulates

2:
has a high affinity and catalyzes most acetaldehyde oxidation

Question 11

high levels of ethanol metabolism

Answer 11

MEOS and alcohol DH forms a large amount of acetaldehyde and a lower amount of acetate

Question 12

Asian flush syndrome

Answer 12

Hereditary deficiency of mitochondrial ALDH-2

thus decreases breakdown of acetaldehyde and thus it accumulates even if ethanol levels are low

flushing, elevated HR, nausea, vomiting

Question 13

high ethanol levels and fasting

Answer 13

Reduced gluconeogenesis due to high NADH/NAD ratio

have high lactate levels due to alanine being converted to lactate and pyruvate cant go into the TCA cycle so it is converted to lactate due to high NADH levels
glutamine is converted to malate

mild hypoglycemia and lactic acidemia

Question 14

hepatic steatosis

Answer 14

an early and common finding in those that chronically drink alcohol

this results due to acetaldehyde toxicity

the release of VLDL is inhibited and lipids accumulate in the liver

Question 15

toxicity of acetaldehyde

Answer 15

tubulins are damaged by this compound, thus VLDL and proteins are not able to leave the hepatocytes

thus proteins and lipid accumulate
lack of blood clotting factors

Question 16

Disulfiram (antabuse)

Answer 16

this drug inhibits aldehyde dehydrogenase

thus ingestion of ethanol increases the amount of acetaldehyde since it cannot be broken down

Question 17

methanol toxicity

Answer 17

methanol is converted to formaldehyde and then formic acid

highly toxic; blindness and death and metabolic acidosis

converted by alcohol dehydrogenase

treatment:
competitive inhibition by ethanol or fomepizole

Question 18

Ethylene glycol toxicity

Answer 18

ethylene glycol is converted to glycolaldehyde by alcohol dehydrogenase and then to glycolic acid and oxalic acid

toxic: renal damage, death, metabolic acidosis

treatment:
competitive inhibition by ethanol or fomepizole

Question 19

acute/ chronic liver disease labs

Answer 19

elevated total, conjugated, and unconjugated bilirubin

conjugated bilirubin in the urine

Question 20

extrahepatic cholestasis labs

Answer 20

serum conjugated bilirubin is high
will be in urine

hard to distinguish between hepatocellular and cholestatic disorder

Question 21

Isolated hyperbilirubinemia

Answer 21

inherited

normal enzyme levels (ALT,AST, ALP)

Question 22

acute liver disease

Answer 22

High ALT levels (cytosolic enzyme)

Question 23

Long-standing chronic alcoholic cirrhosis

Answer 23

High AST levels (2:1)

mitochondrial enzyme

Question 24

ALP

Answer 24

secreted by biliary canaliculi
elevated in intra and extra hepatic cholestasis.. but much higher levels in extra-hepatic

can be elevated during pregnancy, growth, or bone disease

Question 25

GGT

Answer 25

secreted by biliary ducts
induced by alcohol
marker for alcohol consumption

ALP and GGT are VERY high in extra-hepatic cholestasis (dilation of biliary tree)

Question 26

albumin and liver function

Answer 26

chronic liver disease will show a decrease in albumin levels
responsible for ascites and pedal edema

also impacts proteins carried by albumin

Question 27

cirrhosis

Answer 27

will show the beta-gamma bridge

Question 28

liver damage and prothrombin time

Answer 28

increased prothrombin time

reduced clotting factor synthesis and impaired modification of vitamin K dependent clotting factors

Question 29

prothrombin time and cholestasis

Answer 29

reduced bile salt thus less fat and less fat soluble vitamin uptake (Vit K)

impairs post-translational carboxylation of vit K dependent factors

Question 30

chronic liver disease and glucose?

Answer 30

can alter plasma glucose levels

can have either hypo or hyperglycemia

Question 31

advanced liver disease and ammonia

Answer 31

impaired urea formation and an increase in blood ammonia levels

can have hepatic encephalopathy and coma
due to neurotransmitter imbalance and depletion of alpha ketoglutarate

GI bleeding can lead to the encephalopathy

Question 32

fatty liver

Answer 32

excessive TAG deposits in liver cells

due to decreased beta oxidation (high NADH)
increased FA and TAG synthesis
decreased VLDL secretion