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
true or false
halogenated alkyls are toxic upon oxidation, but safe via reduction
FALSE - toxic either way
phogene generated via oxidation and radical species generated via reduction
is methylene chloride safe?
ch2-cl2
NO.
does the same thing as chloroform just to a lesser extent
true or false
all thiols produce sulfenic acid upon oxidation
FALSE
mainly the foreign organic thiols produce this toxicity, but natural thiols like GSH and cysteine are safe
is there any toxicity concern with thiol?
yes - foreign organic thiols can produce sulfenic acid upon oxidation – a very reactive electrophile
what enzyme(s) can catalyze the reduction of sulfoxide to sulfide?
xanthine oxidase
aldehyde oxidase
cyt p450 reductase
-S- <-> -S=O- —> O=S=O
is this any concern?
the oxidation (forward reaction) catalyzed by MFO system usually is not, but the reduction of sulfoxide to sulfide can be catalyzed by -
xanthin oxidase
aldehyde oxidase
cytp450 reductase
this is a potential concern for sulfur toxicity
allyisopropylacetamide
a double bond containing molecule that can irreversibly inhibit Cytochromep450 through heme alkylation
besides allylisopropylacetamide, what else can do heme alkylation?
alkynes
in both scenarios of heme alkylation, what can form?
epoxides
in the case of alkynes it is turned into a carboxylic acid
is the metabolism of anthracycline quinones any concern?
yes
radical oxygen species are formed when molecular oxygen accepts an electron from the oxidation of the molecule (OH to carbonyl) SINGLE ELECTRON TRANSFER – due to cytochromep450 reductase in MFO system
this can generate H2O2, O2. and .OH
what is a class of medications that are anthracycline quinones?
interculating agents – class of anticancer drugs
what specific toxicity occurs from the metabolism of anthracycline quinones
cardiotoxicity from reactive oxygen species
Is there any way for toxicity NOT to be generated from anthracycline quinones?
YES
there is an enzyme - DT-Diaphorase that can supply 2 electrons at once and thus bypass the radical species.
with this enzyme, you can go straight from highly reactive quinone to DIOL – which is chemically safe
NADPH -> NADP is this oxidation or reduction?
oxidation
NADPH is the cofactor involved in….
the redox reaction of anthracycline quinones
what can provide protection against radical oxygen species?
GSH conjugation
what is cyclophosphamide
an alkylating anticancer drug
what is on the right side of the structure of cyclophosphamide
a nitrogen mustard (N and 2 carbon chains with chlorine at the end of each)
true or false
cyclophosphamide is extremely unstable
FALSE
it is stable due to P=O pulling electrons from the nearby N.
no reactive aziridinium species is spontaneously formed
what were the potential phase 1 reactions on cyclophosphamide?
originally, it was thought to undergo hydrolysis via phosphoramidase, but this did not turn out to be the case
there are 2 potential positions for oxidation — the carbon alpha to nitrogen and the carbon alpha to O.
it turned out that only the 4 position (alpha to nitrogen) was oxidized well.
when oxidized, becomes 4-hydroxycyclophosphamide
explain the mechanism of cylclophosphamide metabolism
undergoes oxidation at #4 position to form 4-hydroxycyclophosphamide.
this is a carbinolamine like intermediate that is unstable and the ring breaks open to form =O at one edge (aldehyde)
aldehyde and 4-hydroxycyclophosphamide can go back and forth.
the phosphate ester-like structure is a good leaving group. a proton gets pulled off by any base which causes BETA ELIMINATION and fragmentation of the molecule into
ACROLEIN and a penultimate nitrogen mustard that undergoes other reactions to spontaneously cross links DNA.
what is acrolein?
a metabolite of cyclophosphamide - a highly reactive michael acceptor
_____ is notorious for generating kidney toxicity, and lesser so with _____
iphosphamide, cyclophosphamide does too but not as bad
due to the generation of ACROLEIN
what is the term for when the cyclophosphamide fragments into 2 pieces
tautomerization
what can the michael acceptor be generated from
C=C or C triple bond C connected to N or O or S
true or false
acrolein is a michael acceptor
true
