Phase II reactions Flashcards
phase II is also known as what
conjugation
what is a reducing agent
molecule that donates e to another molecule or atom
what is an oxidizing agent
molecule that accepts e from another molecule
what is an electrophile
e poor (looking to accept e)
what is a nucleophile
e rich (looking to donate e)
electrophiles undergo phase II metabolism by?
glutathione conjugation
what is the conjugating agent of glutathione conjugation
glutathione (GSH)
what is the conjugating enzyme of glutathione conjugation
glutathione-s-transferase
nucleophiles can undergo phase II metabolism by?
- sulfate conjugation
2. glucuronide conjugation
what is the conjugating agent of sulphate conjugation
phosphoadenosine phosphosulfate (PAPS)
what is the conjugating enzyme of sulfate conjugation
sulfotransferase (SULT)
what is the conjugating agent of glucuronide conjugation
UDP glucuronic acid (ADPGA)
what is the conjugating enzyme in glucuronide conjugation
UDP-glucoronyl transferase (UDPGT)
describe glutathione conjugation
route of conjugation of a vartety of electrophile C and endogenous substrates
what are examples of electrophilic X
PAH, HCA, aflatoxin
glutathione (GSH) production is dependent on?
GSH production is dependent upon suffer amino acid synthesis
what is the process of glutathione conjugation
- GST conjugated reactive electrophile with GSH to form a glutathione conjugate
- the glutathione conjugate is lipophilic, so some may partition to bile and can be excreted in feces or enterohepatic circulation
- or, the glutathione conjugate may be metabolized by peptidases, removing glutamate and glycine to form cyctein conjugate (which is more hydrophilic)
- or, N-acetyltransferase may add acetyl group to the cysteine conjugate, forming a mercapturic acid conjugate (very hydrophilic)
how is glutathione regenerated
the pentose phosphate pathway (HMP shut) regenerated NADPH
an increased GSSH to GSH ratio?
is an indication of oxidative stress
what is the route of most nucleophilic conjugation
glucoronide conjugation
when is UDP glucuronic acid (UDPGA) abundant
after a carbohydrate-rich meal when dietary X may be present
what is UDPGA made of
UDP-glucose (an intermediate in glycogen synthesis)
how does the conjugating enzyme for glucoronide conjugation, UDPGT) work
cleaves high energy bond between UDP and glucuronic acid
what is glucuronidation
glucuronide conjugation
describe excretion of glucuronide conjugates
- high molecular weight, low water solubility:
- partition into bile
- excreted via feces or return to the liver via EHC
Low molecular weight, high water solubility
- excreted via urine
if a glucuronide conjugate is high molecular weight with low water solubility where does it go
- partitions into bile
- excreted via feces or return to the liver via EHC
if a glucuronide conjugate is low molecular weight with high water solubility
- excreted via urine
what is the main site of action of glucuronidation
liver
if reaction occurs in the muscle there is no immediate access to EHC
describe the glucuronidaton of morphine
- as a nucleophile, glucuronidation at either the 3- or 6- position
what blocks route of excretion of morphine
synthetic acytylation at either the 3- or 6- position (heroin)
what is sulfation
sulfate conjugation
when does salvation happen
route of some nucleophilic X conjugation as well as conjugation of endogenous substrates (steroid)
what is the conjugating agent of sulfation
phosphoadenosine phosphosulfate
what is PAPS dependent on
dependent on sulphur amino acid status
where are sulfotransferases found
highest expression in reproductive tissues
when does acetylation conjugation
route of conjugation for aromatic amines
for substrates like caffeine, what does acetylation produce
stable conjugate for excretion
for PhIP, what does acetylation produce
a reactive electrophile (primary carcinogen)
when is acetyl-CoA abundant
after a meal
what is the influence of protein deficiency on sulfation
- sensitive to sulphur amino acid status
- leads to decreased sulfation capability
what is the influence of protein deficiency on glutathione conjugation
- GSH is an essential intracellular reducing agent so it is maintained at a certain level despite decreased SAA status
- as protein deficiency becomes more severe eventually lose GSH production/availability
what is the influence of starvation on glutathione conjugation
- decreased GSH production with less availability of amino acid constituents
- increased GST production
what is the influence of starvation on glucuronidation
- decreased UDPGS production with less flux of carbohydrate to glycogen
what foods contain methionine (MET)
- eggs, dairy, animal proteins
- sesame
is acetaminophen an electrophile or nucleophile
nucleophile
what can acetaminophen be conjugated by
glucuronidation
sulfation
then excreted by urine
explain mechanism that acetaminophen metabolism leads to liver cell death
some acetaminophen pool is metabolized by CYP to a reactive electrophile
- which attacks SH groups leading to liver cell death
what are the physiological changes associated with obesity that may affect drug toxicity
- increased circulating blood volumes and hemodynamic changes
- increased risk of cardiomyopathy and atherosclerosis
- alterations in pulmonary function
- changes in large airway anatomy
explain how hydrophilic xenobiotics change with obesity
- the hydrophilic xenobiotics remain in the circulation more readily and will have slower distribution to the tissues
