Detoxification Flashcards
What does detoxify mean?
To render a substance non/less toxic
What is an endobiotic?
Endogenous compound
What is a xenobiotic?
Foreign compound
What are 2 sites of xenobiotic metabolism?
1) Liver (esp for orally ingested)
2) Extrahepatic (lungs, kidney, intestine)
- eg. bacterial transformation of tyrosine to tyramine
What are the 3 main phases of xenobiotic metabolism?
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
What are CYP450s?
Super family of heme proteins found in all cells (except RBC and skeletal muscles)
Where are CYP450 found?
In mitochondria and ER of all cells (except RBC and Skeletal muscles)
What are 2 endogenous functions of CYP450s?
1) Biosynthesis of steroids
2) Metabolisms of FAs and its derivates (prostaglandins, leukotrienes, retinoids)
What are 2 reactions catalysed by CYPs?
1) Hydroxylation (aliphatic and aromatic)
2) Epoxidation
3) Deamination
What is required for hydroxylation and epoxidation rxn catalysed by CYPs?
1) O2
2) NADPH
Why is benzopyrene carcinogenic?
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
Why is aflatoxin carcinogenic?
After metabolism by CYP (hydroxylation and epoxidation) → forms metabolite (Aflatoxin B1, 8-9 epoxide)
9-10 epoxides can form an DNA-adduct
→ mutations → cancer
Why is naphthalene carcinogenic?
1) Naphthalene → NPO by CYP
2) NPO can be metabolised to form naphthoquinones → forms DNA and protein adducts → mutations → cancer
What are 3 phase 1 enzymes?
1) Cytochrome P450
2) Epoxide hydrolase
3) Esterases
What are 2 xenobiotics metabolised by CYPs?
1) Aflatoxin
2) Benzopyrene
3) Naphthalene
What is an example of a xenobiotic metabolised by esterases?
1) Acetylsalicylic acid (Aspirin)
2) Heroine
Phase II detoxification reactions require the substrate to have _________________.
Functional groups present
(eg. -OH, -COOH, -NH2, -SH, etc.)
Phase I rxns (more/less) frequently produce toxic metabolites compared to phase II rxns.
Phase I > Phase 2
What are 4 examples of phase 2 reactions?
1) Glucuronidation (UGTs)
2) Sulphation (SULTs)
3) Glutathione conjugation (GSTs)
4) Acetylation (NATs)
5) Amino-acid conjugation (glycine conjugation)
Glucuronidation rxns are catalysed by ________________ found on _________________.
UGTs
Found on ER
What are 3 substances that are metabolised by UGT?
1) Bilirubin
2) Steroids
3) Bile salts
4) Catecholamines
Other than UGTs, what is needed for glucuronidation and where does it come from?
Need UDP-glucuronic acid (UDPGA) from:
1) UTP + G1P → UDP-glucose pyrophosphorylase → UDP-glucose
2) UDP-glucose + 2NAD+ → UDP-glucose dehydrogenase → UDPGA + 2NADH + H+
What is an example of a xenobiotic metabolised by UGT?
1) Morphine
2) Reseratrol (from red wine)
Sulphation rxns are catalysed by ________________ found on _________________.
SULTs
Found on:
1) Cytosol (for small molecules)
2) Golgi membrane (for carbohydrates and proteins)
Unlike UGTs and CYPs, SULTs are (not) inducible and have a (high/low) affinity for substrates but in a (high/low) capacity process.
SULTS:
- not inducible
- high affinity for substrate but low capacity
Other than SULTs what is needed for sulphation and where does it come from?
PAPS
1) ATP + SO42- → ATP sulfurylase → APS + PPi
2) APS + ATP → APS-Kinase → PAPS + ADP
What are 2 xenobiotic substrates metabolised by sulphation/SULTs?
1) Resveratol (in red wine)
2) Bisphenol A
Glutathione conjugation rxns are catalysed by ________________ found on _________________.
GSTs
Found in:
1) Cytosol
2) SER
3) Mitochondria
What is the end product of all glutathione conjugation rxns?
Mercapturic acid (N-acetylcysteine conjugate)
What is a xenobiotic that is metabolised by GSTs/in glutathione conjugation?
1) Quercetin
2) Naphthalene
How is mercapturic acid formed?
1) Glutathione conjugation by GSTs
2) Removal of flanking amino acids → cysteine-S-conjugate
3) Acetylation by NAT → mercapturic acid
Other than NATs what is needed for acetylation and where does it come from?
Acetyl-CoA
- from metabolic pathways (eg. glycolysis, ß-oxidation, etc.)
Substrates for acetylation by NATs require _____________.
-NHx (amino group)
What is an example of xenobiotic metabolised by NATs/acetylation?
1) Isoniazid
2) Propanolol
3) Cysteine S-conjugate
Substrates for glycine conjugation require _____________.
-COOH
What enzyme catalyses acetylation?
NATs (N-acetyl transferases)
What enzyme catalyses glycine conjugation?
Glycine N-acyltransferase
What is the process of glycine conjugation?
1) Activation to CoA derivative
2) Glycine conjugation
3) Excretion
What is an example of a xenobiotic metabolised by Glycine N-acyltransferase in glycine conjugation?
1) Aspirin
2) Benzoate
P-gp (P glycoprotein) transporter facilitates ____________ export of xenobiotics in enterocytes, hepatocytes and renal epithelial cells to be excreted.
ATP-dependent transport
MRP transporters facilitate the ATP-dependent transport of ________________ out of (which cell type) into bile or blood.
Conjugated molecules (eg. glutathione, glucuronide, sulphate conjugates)
out of hepatocytes
Describe the metabolism of Aspirin.
1) Esterase → remove acetyl group → Salicylic acid
2) Phase 2 rxns (glycine conjugation (#1), sulfation, glucuronide conjugation) → Mainly salicyluric acid (glycine conjugate)
3) Excreted
Describe the metabolism of paracetamol.
1) Phase 2 rxns (glucuronide conjugation or sulfation)
2) Excreted
Describe what happens when there is a paracetamol overdose and how is it treated?
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
