LEC 51 Xenobiotic Metabolism

Question 1

What are some examples of xenobiotic compounds?

Answer 1

Slide 5

Question 2

What are the characteristics of xenobiotic compounds?

Answer 2

• hydrophobic, bulky
  *uncertainty surrounding how they might react in different circumstance

Question 3

What happens during functionalization?

Answer 3

• Introduce or expose polar group
• Creates nucleophiles **
• Oxidations & bond cleavages

Question 4

What happens during conjugation?

Answer 4

• Couple polar group (increase solubility!)
• Nucleophilic-electrophilic reaction (utilizes transferase enzymes)

Question 5

What happens in transport in xenobiotic metabolism?

Answer 5

• Localization is altered tagging it for excretion
  *ABC transporters

Question 6

What enzymes catalyze the oxidation reactions?

Answer 6

• Cytochrome P450s (P450, CYP)
• Flavin monooxygenases (FMO)
• Alcohol dehydrogenase (ADH)
• Aldehyde dehydrogenases (ALDH)

Question 7

Describe cytochrome P450.

Answer 7

• Most important metabolizer of drugs!!!
• Largely oxidizes compounds, but can also form epoxides
• Membrane-bound heme (Fe) protein complex
• Lipophilic substrates: Endobiotic, e.g. steroids and arachidonic acid; Xenobiotic, e.g. food additives, environmental pollutants, DRUGS

Question 8

Whats the role of cytochrome P450 in xenobiotic metabolism?

Answer 8

• LIVER, lung, kidney, gastrointestinal tract, skin
• Dominated by CYP1, 2, and 3 family (> 11 families in humans)
• Overlapping substrate specificities common, i.e. LOW specificity
• Monooxygenase reaction

Question 9

What factors can affect Xenobiotic metabolism?

Answer 9

• Age, diet, gender, state of health
• Polymorphisms (genetic variants)
• Drug-drug interactions!! (toxic metabolites)
• Competitive inhibition of substrates
• Enzyme induction or stabilization
• Routes of drug administration (pill, injection, etc.)

Question 10

How can acetaminophen create toxic metabolites?

Answer 10

If you mix alcohol with acetaminophen it can be oxidized to reactive NAPQI –> depletes glutathione –> loss of antioxidant capacity

Question 11

What are some examples of conjugation?

Answer 11

Glucuronidation: UDP-Glucuronosyl transferase (aglycones: bilirubin/ jaundice)
- major route of conjugative metabolism & 2nd in overall importance for drug metabolism
Sulfate Conjugation: Sulfotransferase (SULT) noninducible
Glutathione Conjugation: Glutathione S-Transferase
Acetylation: N-acetyl transferase (NAT1 in liver & NAT 2 in colon)