Bioactivation of xenobiotics to reactive metabolites
23 important questions on Bioactivation of xenobiotics to reactive metabolites
What is the difference between phase I metabolism and phase II metabolism?
phase II: coupling the xenobiotic with an endogenous substrate
What are the phase I enzymes and what is their function?
- Flavin-dependent monooxygenase (FMO): N- and S- oxidation (not C)
- peroxidase: reduction of hydroperoxides to alcohol
- carboxylesterase;amidase: hydrolysis of ester or peptide bonds
- alcohol dehydrogenase ADH: oxidation of alcohols to aldehyde
- epoxide hydrolase: hydrolysis of epoxides to dihydrodiols
What are the phase II enzymes and their substrate conjugations?
- sulfotransferases (SULT): Transfer of sulfate (from phosphoadenosine phosphosulfate) to xenobiotic.
- N-acetyltransferase (NAT): Transfer of acetate (from acetyl-CoA) to xenobiotic
- Glutathione-S-transferase (GST): Transfer of glutathione to xenobiotic
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What is the function of CYP?
What are the molcular mechanisms behind CYP induction?
- cyp3A is regulated by pregnane x receptor (PXR)
- other forms are regulated by the HNF family.
- cyp2B6, 3a and 2c is mediated via CAR (constitutively active receptor)
What are the molecular reasons behind PXR binding?
2) The receptor's binding pocket is accessible through a gated channel
3) Cavity is extremely hydrophobic but also hydrogenbonds are possible
4) The structure of the receptor allows for binding in multiple orientations.
What are the mechanisms behind furanocoumarin-induced cyp3a4 inhibition?
What are the mechanisms behind 4-ipomeanol induced lung injury?
What are the mechanisms behind clozapine induced agranulocytosis?
What is uridine-diphosphate glucuronosyltransferase?
- Sometimes also toxification can occur e.g. acyl glucuronides when carboxylic acids are glucuronidated.
- UGT1 and UGT2.
- Substrate is called an aglycone.
- UGT1 conjugates also billirubine.
What are the mechanisms behind bioactivation and carcinogenicity of 2-naphtylamine?
2) UGT catalyzes the conversion of these N-hydroxylated aromatic amines to the N-glucuronide which are stable at normal pH. They are excreted throughout the body.
3) Because the urine is slightly acidic the N-glucuronides are hydrolyzed in the urine and degraded to a highly nitrenium ion that are electrophyllic and DNA reactive.
What are the mechanisms behind tamoxifen bioactivation and carcinogenicity in rats?
- however, alpha-hydroxy-tamoxifen is a substrate for SULT and can readily undergo O-sulfation.
- This sulfate group is readily cleaved off and a carbocation is formed.
- This is only in rats the case because they cannot glucuronidate the alpha-hydroxy tamoxifen and they can alphahydroxylate much faster than humans.
For which 2 reasons are NAT-mediated reactions important in toxicology?
2) There are large differences between humans in NAT expressions that can modulate metabolism and therefore also toxicity of substrates.
What is the mechanim behind benzidine bioactivation?
2) N-acetylation
3) Intramolecular acyl transfer to acetoxyarylamine. This can be converted to a carbocation.
What are the mechanisms behind susceptibility to INH hepatotoxicity and perpheral neuropathy?
2) hydrolysis
3) NAT2 activity or CYP2E1. Via CYP2E1 -> hepatotoxicity.
What are mechanisms of acrylamide metabolism and detoxication?
- Both acrylamide and the expoxide can be conjugated to glutathione a GST dependent reaction, this last reaction eliminates the toxicant.
What are the mechanisms behind ethylene dibromide-s-conjugate toxicity?
What are the mechanisms behind benzohydroquinone-glutathione-S-conjugate nephrotoxicity?
2) conjugation of benzoquinone with GSH.
When the GS conjugates reach the kidney they can become cleaved into two amino acids. Firts gamma glutamyl transpeptidase which cleaves off the glutamate residue, then dipeptidase DPP which cleaves off the removal of glycine. Only cysteine will remain which will rapidly be taken up in the proximal tubular cell by the amino acid transporter. Inside the cell the cysteine conjugate becomes oxidized to the substituted benzoquinone.
What is the mechanism fo hexachlorobutadiene toxicity?
What is cysteine beta lyase?
What are the mechanisms behind coumarin bioactivatin and inactivation?
- It can be detoxified by GSH
What is the mechanism behind nephrotoxicity of APAP?
- detoxification with glutathion
- cleaving of glutamyl moiety and glycine
- APAP-cys which is reactive.
Which proteins are upregulated during a stress response?
- immunophillins
- acute phase proteins
- heat shock proteins.
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