Phase 2 biotransformation Flashcards
what does phase 2 lead to
large increase in hydrophilicity and excretion
what phase 2 reaction do electrophilic xenobiotics undergo
glutathione conjugation
what phase 2 reaction do nucleophilic xenobiotics undergo
glucuronidation CoA conjugation Sulfonation AA conjugation Methylation Acetylation
what does the synthesis of glutathione need
required energy
what is GSH
glutathione
what family is glutathione in
glutathione s-transferase (GST)
what type of reaction does glutathione conjugation start
reduction
describe glutathione conjugation reducing capacity in the cell
- can reduce ROS
-
what regenerates glutathione
glutathione reductase (GSSG=2GSH)
what are the xenobiotic substrates of glutathione conjugation
- electrophile
- electrophilic C or heteroatom (O,N,S)
what are the three common characteristics of substrates for glutathione conjjgation
- hydrophobic
- contain an electrophilic atom
- react nonenzymatically with GSH at some measurable rate
why do electrophiles need to be detoxed
electrophiles are potentially toxic by binding to critical nucleophiles (proteins, nucleic acids)
all biotransforming enzymes have the potential to create what
reactive intermediates
what conjugation enzyme family is glucuronidation in
UDP-glucuronosyltransferase (UGT)
where is glucuronidation located
lumen of the ER (liver, kidney,GI,lung,skin,brain,spleen)
what families are the major xenobiotic metabolizing UGTs
UGT1 UGT2
what are the substrates for glucuronidation
- contain nucleophilic C or heteroatom (O,N,S)
- small compounds containing aliphatic alcohols and phenols, carboxylic acids, primary and secondary aromatic and aliphatic amines, free thiol groups)
examples of glucuronidation substrates
propofol, acetaminophen, morphine, carbamazepine
purpose of glucuronidation detoxification
drug metabolism for excretion
or
activation to a therapeutic metabolite
explain influence fasting can have on glucuronidation
fasting decreases the cofactor UDPGA and can predispose to acetaminophen toxicity
what induces UGTs
nicotine, cabbage, brussels sproats
what enhances glucuronidation of acetaminophen
nicotine, cabbage, brussel sproats
what inhibits UGTs
valproic acid inhibits UGTs, increasing plasma AUC for the UGT/glucuronidation targets lorazepam and carbamazepine
what is carbamazepine
anticonvulsant
describe phase 1 pathway of carbamazepine
- CBZ induces CYP3A4
2. CBZ metabolism hindered by CYP3A4 inhibitors
describe phase 2 pathway of carbamazepine
- CBZ metabolism enhanced by UGT inducers
what conjugating enzyme family is sulfation
sulfotransferase (SULT)
describe xenobiotic metabolizing SULTs
soluble and located in cytoplasm
what are the two main SULT families
SULT1- phenols, catecholamines
SULT2- polycyclic aromatic hydrocarbons
what are the substrates of sulfonation
many endogenous and xenobiotics that undergo O-glucuronidation
compare sulfation to glucuronidation
sulfation has high affinity, low capacity versus glucuronidation
what xenobiotic substrates can be activated to therapeutic metabolite by sulfation
minoxidil, morphine
describe inhibition of SULTs
coadministration of acetaminophen and ethinyl estradiol
- compete for the SULT, increasing the AUC for each drug/ or sends the drug to an alternative biotransformation pathway
in what way is acetaminophen biotransformation hindered by ethinyl estradiol
- they compete for SULTs which can send acetaminophen toward glucuronidation or CYP450
what induces SULTs
coadministration of rifampin and ethinyl estradiol
how does rifampin influence ethynyl estradiol transformation
rifampin can increase the clearance of ethinyl estradiol by 190% which decreases its AUC and plasma concentration
