Second set of slides Flashcards
under normal conditions, acetaminophen is a substrate for which phase 2 metabolic reactions?
glucuronidation
sulfation (contains phenol)
if too much is taken, acetaminophen can cause ____ toxicity
hepato
when given a structure, what’s the very first thing you should look for?
polar functional groups
true or false
when acetaminophen is ingested, it goes through both sulfation and glucuronidation right away
true
substrate for sulfation
phenol
under normal conditions, does acetaminophen undergo phase 1 metabolism?
NO - only if too much is taken
what is a typical michael acceptor
an alpha-beta unsaturated carbonyl (or equivalent)
michael acceptors (alpha beta unsaturated carbonyls) are excellent substrates for which conjugation pathway?
GSH because they are chemically reactive
true or false
michael acceptors are very reactive
TRUE
explain the different pathways of acetaminophen metabolism
under normal conditions: phase 1 is bypassed and acetaminophen immediately undergoes both glucuronidation and sulfation
if too much is taken and the system becomes saturated, there are other pathways.
- arene oxide formation (oxidation) and formation of DIOL, to form a “catechol metabolite”
- oxidized to 1,4 Imidoquinone intermediate. this has THREE POTENTIAL FATES:
- Cleared through GSH conjugation
- unknown pathway that leads to cell death
- it itself binds to liver tissue macromolecules OR gets hydrolyzed and that compounds covalently binds to liver tissue macromolecules (both cause cell death)
if the toxic metabolite (1,4 imidoquinone) undergoes GSH conjugation, what are the 4 potential conjugates?
cysteine, mercapturic acid, methylthio, and methylsulfoxide conjugates
what are the michael acceptor(s) in the metabolism of acetaminophen?
the 1,4 imidoquinone intermediate and the compound that results from the hydrolysis of this intermediate
explain how phenacetin is metabolized
does NOT have a sufficiently polar functional group (like acetaminophen), so it must undergo phase 1.
the 2 phase 1 reactions that occur are N-hydroxylation and Hydrolysis to form a primary amine (which gets N-hydroxylated) to form HYDROXYLAMINE
hydroxylamine then gets oxidized to nitroso, and nitroso gets reduced back to hydroxylamine - back and forth. this is coupled with HEMOGLOBIN. THUS, as nitroso gets reduced, Ferrous gets oxidized to FERRIC (Fe3+)
ferric is BAD - “methemoglobin” which is not as efficient as typical hemoglobin – leads to oxygen deficiency
how is phenacetin toxic?
2 ways:
- amines can lead to nephrotoxicity
- The oxidation-reduction of nitroso <-> hydroxylamine is coupled with hemoglobin. This causes Ferrous to get oxidized to Ferric +3 (methemoglobin)
hydrazine
N-N
what can you say about the metabolism of hydrazines
they are very nasty and toxic when metabolized
produce radicals and carbocations
How can oxidative N-dealkylation be toxic?
the unstable carbinolamine intermediate can be DEHYDRATED IF R SUBSTITUENTS ARE BULKY – go back and forth between a schiff base (C=N+) reactive species which can readily be hydrated or pick up any nucleophile – potential toxicity concern
Arene oxide can form….
a diol or a phenol
teratogenic drugs often exist due to _______ producing molecules
ARENE OXIDE
arene oxides are usually readily intercepted, but if not it’s a teratogenic concern
true or false
furan can form an arene oxide
TRUE
arene oxides can be heteroaromatic as well as aromatic
chloroform formula
CHCl3
chloroform was once used for what?
decaffeinated coffee
explain why chloroform isnt used anymore
can form phosgene – a chemically reactive acyl halide. has 2 good leaving groups.
carbon tetrachloride was introduced to replace chloroform on what basis? was it successful?
carbon tet has no available hydrogen, so it was thought that oxidation would not occur and thus the toxic phosgene (acyl chloride) would not be generated
however, carbon tet can still generate toxic radical species upon reduction
