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Metabolism and Biochem > Detoxification > Flashcards

Detoxification Flashcards

1
Q

What does detoxify mean?

A

To render a substance non/less toxic

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2
Q

What is an endobiotic?

A

Endogenous compound

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3
Q

What is a xenobiotic?

A

Foreign compound

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4
Q

What are 2 sites of xenobiotic metabolism?

A

1) Liver (esp for orally ingested)

2) Extrahepatic (lungs, kidney, intestine)
- eg. bacterial transformation of tyrosine to tyramine

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5
Q

What are the 3 main phases of xenobiotic metabolism?

A

1) Phase 1:
- metabolites serve as substrates for phase 2 rxn

2) Phase 2:
- results in polar metabolites for phase 3

3) Phase 3:
- Elimination out of cell and body

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6
Q

What are CYP450s?

A

Super family of heme proteins found in all cells (except RBC and skeletal muscles)

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7
Q

Where are CYP450 found?

A

In mitochondria and ER of all cells (except RBC and Skeletal muscles)

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8
Q

What are 2 endogenous functions of CYP450s?

A

1) Biosynthesis of steroids
2) Metabolisms of FAs and its derivates (prostaglandins, leukotrienes, retinoids)

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9
Q

What are 2 reactions catalysed by CYPs?

A

1) Hydroxylation (aliphatic and aromatic)
2) Epoxidation
3) Deamination

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10
Q

What is required for hydroxylation and epoxidation rxn catalysed by CYPs?

A

1) O2
2) NADPH

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11
Q

Why is benzopyrene carcinogenic?

A

After metabolism by CYP (hydroxylation and epoxidation) → forms metabolite (Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide)

9-10 epoxides can form an DNA-adduct

→ mutations → cancer

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12
Q

Why is aflatoxin carcinogenic?

A

After metabolism by CYP (hydroxylation and epoxidation) → forms metabolite (Aflatoxin B1, 8-9 epoxide)

9-10 epoxides can form an DNA-adduct

→ mutations → cancer

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13
Q

Why is naphthalene carcinogenic?

A

1) Naphthalene → NPO by CYP
2) NPO can be metabolised to form naphthoquinones → forms DNA and protein adducts → mutations → cancer

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14
Q

What are 3 phase 1 enzymes?

A

1) Cytochrome P450
2) Epoxide hydrolase
3) Esterases

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15
Q

What are 2 xenobiotics metabolised by CYPs?

A

1) Aflatoxin
2) Benzopyrene
3) Naphthalene

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16
Q

What is an example of a xenobiotic metabolised by esterases?

A

1) Acetylsalicylic acid (Aspirin)
2) Heroine

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17
Q

Phase II detoxification reactions require the substrate to have _________________.

A

Functional groups present
(eg. -OH, -COOH, -NH2, -SH, etc.)

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18
Q

Phase I rxns (more/less) frequently produce toxic metabolites compared to phase II rxns.

A

Phase I > Phase 2

19
Q

What are 4 examples of phase 2 reactions?

A

1) Glucuronidation (UGTs)
2) Sulphation (SULTs)
3) Glutathione conjugation (GSTs)
4) Acetylation (NATs)
5) Amino-acid conjugation (glycine conjugation)

20
Q

Glucuronidation rxns are catalysed by ________________ found on _________________.

A

UGTs
Found on ER

21
Q

What are 3 substances that are metabolised by UGT?

A

1) Bilirubin
2) Steroids
3) Bile salts
4) Catecholamines

22
Q

Other than UGTs, what is needed for glucuronidation and where does it come from?

A

Need UDP-glucuronic acid (UDPGA) from:

1) UTP + G1P → UDP-glucose pyrophosphorylase → UDP-glucose

2) UDP-glucose + 2NAD+ → UDP-glucose dehydrogenase → UDPGA + 2NADH + H+

23
Q

What is an example of a xenobiotic metabolised by UGT?

A

1) Morphine
2) Reseratrol (from red wine)

24
Q

Sulphation rxns are catalysed by ________________ found on _________________.

A

SULTs
Found on:
1) Cytosol (for small molecules)
2) Golgi membrane (for carbohydrates and proteins)

25
Q

Unlike UGTs and CYPs, SULTs are (not) inducible and have a (high/low) affinity for substrates but in a (high/low) capacity process.

A

SULTS:
- not inducible
- high affinity for substrate but low capacity

26
Q

Other than SULTs what is needed for sulphation and where does it come from?

A

PAPS
1) ATP + SO42- → ATP sulfurylase → APS + PPi

2) APS + ATP → APS-Kinase → PAPS + ADP

27
Q

What are 2 xenobiotic substrates metabolised by sulphation/SULTs?

A

1) Resveratol (in red wine)
2) Bisphenol A

28
Q

Glutathione conjugation rxns are catalysed by ________________ found on _________________.

A

GSTs
Found in:
1) Cytosol
2) SER
3) Mitochondria

29
Q

What is the end product of all glutathione conjugation rxns?

A

Mercapturic acid (N-acetylcysteine conjugate)

30
Q

What is a xenobiotic that is metabolised by GSTs/in glutathione conjugation?

A

1) Quercetin
2) Naphthalene

31
Q

How is mercapturic acid formed?

A

1) Glutathione conjugation by GSTs
2) Removal of flanking amino acids → cysteine-S-conjugate
3) Acetylation by NAT → mercapturic acid

32
Q

Other than NATs what is needed for acetylation and where does it come from?

A

Acetyl-CoA
- from metabolic pathways (eg. glycolysis, ß-oxidation, etc.)

33
Q

Substrates for acetylation by NATs require _____________.

A

-NHx (amino group)

34
Q

What is an example of xenobiotic metabolised by NATs/acetylation?

A

1) Isoniazid
2) Propanolol
3) Cysteine S-conjugate

35
Q

Substrates for glycine conjugation require _____________.

A

-COOH

36
Q

What enzyme catalyses acetylation?

A

NATs (N-acetyl transferases)

37
Q

What enzyme catalyses glycine conjugation?

A

Glycine N-acyltransferase

38
Q

What is the process of glycine conjugation?

A

1) Activation to CoA derivative
2) Glycine conjugation
3) Excretion

39
Q

What is an example of a xenobiotic metabolised by Glycine N-acyltransferase in glycine conjugation?

A

1) Aspirin
2) Benzoate

40
Q

P-gp (P glycoprotein) transporter facilitates ____________ export of xenobiotics in enterocytes, hepatocytes and renal epithelial cells to be excreted.

A

ATP-dependent transport

41
Q

MRP transporters facilitate the ATP-dependent transport of ________________ out of (which cell type) into bile or blood.

A

Conjugated molecules (eg. glutathione, glucuronide, sulphate conjugates)
out of hepatocytes

42
Q

Describe the metabolism of Aspirin.

A

1) Esterase → remove acetyl group → Salicylic acid

2) Phase 2 rxns (glycine conjugation (#1), sulfation, glucuronide conjugation) → Mainly salicyluric acid (glycine conjugate)

3) Excreted

43
Q

Describe the metabolism of paracetamol.

A

1) Phase 2 rxns (glucuronide conjugation or sulfation)

2) Excreted

44
Q

Describe what happens when there is a paracetamol overdose and how is it treated?

A

Paracetamol conc. > rate of metabolism by UGT and SULT

→ Converted by CYP to NAPQI (toxic intermediate)

→ can form covalent bond with proteins and DNA → adducts → cell death

Treated with N-acetylcysteine (precursor of glutathione)
↑↑NAPQI can undergo glutathione conjugation → mercapturic acid

Metabolism and Biochem (8 decks)

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