Alcohol & xenobiotic

Question 1

Drug metabolism involves 2 phases

Answer 1

• Phase 1: increasing the drug’s hydrophobicity
  
  • microsomal cytochrome P450 oxidases
  • either oxidative N-dealkylations (morphine) or hydroxylated (propanolol) or reduction (methadone)
• Phase 2: conjugating the functional groups formed during Stage I, usually by glucoronidation or sulphation, which increases the solubility of drug metabolite

Question 2

Phase 1 rxn: CYP family

Answer 2

• Phenobarbital (anti-epileptic) accelerates CYP synthesis & increases drug metabolism
• Carbamazepine (anti-epileptic) metabolized by CYP3A4
• Chronic ethanol stimulates CYP2E1 (MEOS system)
• Erythromycin & CAT inhibit CYP
• Statins metabolised by CYP3A4 but grapefruit inhibits CYP3A4

Question 3

Mitochondrial CYPs

Answer 3

• hydroxylations of steroids
• liver hydroxylates cholesterol in bile acid synthesis
• dex of drugs using NADPH as a reducing equivalent
• new OH group on drug provides a conjugation site for phase 2 rxn

Question 4

Phase 2 rxn

Answer 4

Glucuronidation:

Drug-OH + UDP-glucuronic acid -> Glucuronic acid-drug compliance

Sulfation:

Drug-OH + phosphoadenosine phosphosulfate -> sulfate ester-drug conjugate

• Asprin is metabolized as fatty acids

Question 5

CYP rxn generate free radicals

Answer 5

• ROS include hydrogen peroxide (formed by partial reduction of molecular O2)
• cause oxidative stress to DNA, proteins & unsaturated fatty acids
• superoxide radical may occur in cytosol as a result of microsomal CYP

Question 6

Paracetamol (acetaminophen/tylenol overdose)

Answer 6

• Liver normally conjugates with glucuronic acid or sulphate.
• If a Pt takes an overdose of paracetamol, the conjugation process is overwhelmed, instead it is oxidised to N-AcetylBenzoquinoeimine (NABQI or NAPQI) by CYP2E1 -> Toxic
• NABQI rapidly detox by a conjugation rxn catalyzed by Glutathione S-transferase involving glutathione
• Rx: N-AcetylCysteine may overcome Paracetamol toxicity by stimulating GSH
• EtOH induces CYP2E1 and so alcoholics taking paracetamol may produce more the toxic NAPQI

Question 7

Aflatoxin B1

Answer 7

• Aflatoxins are a generic group of toxins produced by Aspergillus flavus
• specifically cause liver damage and are associated with eating moldy food, which is common in poverty-stricken areas such as tropics where the high humidity enhances fungal growth
• CYP3A4 & CYP1A2 activation of Aflatoxin B1 to 2,3-epoxide, a potent carcinogen, that forms adducts with guanine nucleotides
• p53 gene known to be affected & leads to liver cancer

Question 8

EtOH metabolism by ADH

Answer 8

• ADH is the primary path for ethanol metabolism; CYP2E1 & catalase are minor pathways
• NADH will accumulate when ethanol is metabolized by ADH -> lactate production from Pyr by LDH-5 -
  
  • Pyr unable to be used as gluconeogenic precursor
  • lactic acidosis
• high NADH:NAD+ ratio inhibits acyl Beta-oxidation, resulting in increased hepatic TAG synthesis (hepatic steatosis) & VLDL production
• high hepatic NADH:NAD+ ratio will also lead to deamination of glucogenic amino acids producing a carbon skeleton that is converted into either pyruvate or intermediates of TCA cycle -> driving LDH & malate dehydrogenase in the wrong direciton ->low OAA levels will lead to ketoacidosis

Question 9

Hepatic glycerol metabolism in alcoholic liver damage

Answer 9

• Alcohol predisposes body to make fat (TAG)
• blood glycerol is phosphorylated by Glycerol Kinase on entering liver
• Glycerol 3-P normally directed into glycolysis via DHAP, but again hepatic accumulation of NADH shifts the eq. of the rxn away from DHAP

DHAP + NADH H+ -> Glycerol 3-P + NAD+

• Glycerol 3-P diverted into TAG synthesis

Question 10

Short- and Long-term metabolic effects of alcohol consumption

Answer 10

Short-term

• Reduced GNG (hypoglycemia) with lacticacidemia
• Increased Acetyl-CoA production & TAG synthesis
• Decreased NAD+ availability may affect TCA (E production may be compromised)
• Elevated blood lactate levels competes with uric acid renal excretion (elevated blood uric levels will lead to gout)

Long-term

• Acetaldehyde binding to lipids & proteins (via lysyl epsilon amino group) forming unstable acetaldehyde-Schiff base adducts

Question 11

Chronic alcoholic liver damage

Answer 11

• liver damage occurs when elevated hepatic levels of acetaldehyde results in the formation of Schiff base adducts with macromolecules (i.e. crosslinks)
• acetaldehyde at high levels will enter the blood and form acetaldehyde adducts with blood proteins
• chronic alcohol also increases hepatic TAG & VLDL production
• ethylation of apo B-100 renders LDL immunogenic, accelerating their by clearance by macrophages -> foam cells -> increased atherosclerotic effect

Question 12

3 stages of alcohol-induced liver disease

Answer 12

• Fatty liver (reversible)
• Fibrosis: excessive collagen by stellate cells (reversible)
• Cirrhosis (irreversible)