L45 Biochemistry of Liver

Question 1

plasma proteins synthesized by the liver

Answer 1

serum albumin- 12g/day, 25% of hepatic protein synthesis and one of the most abundant plasma protiens playing important role in oncotic pressure.

transport protiensL apolipoproteins, protease inhibitor, fibrinogen and other clotting factors

hepatic lipases hydrolyze the remaining tags in IDL

liver main functionsL metabolism of phospholipids and chol
excrete lipophilic wasts
drug met
hormone degredation

Question 2

sources of blood to liver

Answer 2

hepatic portal vein: unoxygenated nutrient rich blood (70%)

hepatic artery: low nutrients oxygen rich blood (30%)

Terminal branches mix together

Question 3

periportal and perivenous hepatocytes

Answer 3

periportal:

• extrahepatic hormones
• key glucose liberating enzymes
• key fatty acid oxidation enzymes
• RER and GA
• MITO
• aa catabolism, box, gng, urea
• low IG ratio
• CPSI, rate limiting enzyme for urea cycle, high Km for NH3, detox liver of NH3, creates urea for secretion

perivenous

• key glycolytic enzymes
• key fatty acid synthesizing enzymes
• SER high for FA synthesis, cholesterol, bile salts as well as drug metabolism
• less mito
• lactate production and HMP shunt-supplies NADPH for FA, chol and bile salt synth
• high IG ratio
• GLUTAMINE SYNTHESIS via GLUTAMINE SYNTHETASE (cytoplasm), low Km for NH3, Mop up, glutamine sent to kidney used to adjust urinary pH

Question 4

Xenobiotic drug metabolism general

Answer 4

strategy: make them more hydrophilic so they can be excreted easier in urine or bile

often directly into bile

can be further metabolized by intestinal flora, amphipathic compounds often reabsorbed via enterohepatic circulation and reexcreeted by liver

PERIVENOUS HEPATOCYTES

• SER
• HMP shut (NADPH needed for drug metabolism and N202 reduction)
• minimal ATP

Question 5

Phases of drug metabolism

Answer 5

Phase I hydrophilic functional group (OH, NH2, SH) introduced by SER enzymes

• cytochrome p450 monooxygenases (CYP)
• low substrate specificity
• hydroxylates xonobiotic drugs ysing NADPH as reducing equivalent. REQUIRES O2, and superoxide radical intermediate
• O2 free radicals, coupled with depletion of GSH can lead to drug induced perivenous cell necrosis
• necrosis from byproduct of drug met.

Phase II: conjugation reactions in cytosol where a hydrophilic group is added to xonobiotic
-glucuronidation (add glucuronic acid) by UDP GLUCORONOSYLTRANSFERASE

purpose of both? increase water solubility of lipophilic xenobiotic. Pro drugs can also become drugs.

Question 6

how are endogenous lipophilic compounds broken down

Answer 6

same as xenobiotics!

bile sale synthesis
Phase I is hydroxylation of the steroid nucleus catalyzed by cyto P450 enzymes (ie 7alpha hydroxylase)

phase II is the conjucation of the bile acids with either glycine or taurine

conjufated entities are excreted directly into bile

Question 7

Hepatic Alcohol Metabolism

Answer 7

two paths (ethanol)

1st: located in cytosol most tissues have AH (alcohol dehydrogenase) to acetaldehyde
- low Km 5mg/dL and
- then aldehyde dehydrogenase to acetate
- 2 moles NADH and one mole acetic acid produces per mol of alcohol oxidized

• acetylaldehyde is TOXIC intermediate, role in hangover, Asians do not have aldehyde dehydrogenase and accumulation of acetaldehyde
• high km =6 fold decrease in risk of alcoholism

2nd: habitual drinkers and enzymes of perivenous hepatocytes
- CYP2E1 (MEOS) catalyzes first step, NADPH required
- CYP2E1 has a higher Km compared to ADH, ADH is working at Vmas, after just two drinks, CYP2E1 is most effective at alcohol levels above 0.1 (3-5 drinks)
- alcohol dehydrogenase catalyzes second reaction (NADH cyto produced)
- both make acetic acid, and acetaldehyde are the same and if theyre married

Question 8

etoh metabolism and drug metabolism

Answer 8

competitive inhibition

cytochrome p450 is not induced
figure a, both paths fine
Figure b, comp inhibition os CYP2E1

when cytochrome p450 IS induced
figure c (low ethanol with the drug) both paths operate dut drug metabolism is enhanced due to increased CYP2E1, anesthesia wears off faster
-acetaminophen is dangerous due to rapin drug met and increased free rad prod leading to GSH def
-increase in CYP2E1 may potentially account for increased conversion of endogenous wek androgens  (test atrophy) (alcoholics)

figure d. high ethanol levels and drugs
both competing for CYP2E1 meaning EXHAGGERATED pharmacological effect.