Phase 2 biotransformation

Question 1

what does phase 2 lead to

Answer 1

large increase in hydrophilicity and excretion

Question 2

what phase 2 reaction do electrophilic xenobiotics undergo

Answer 2

glutathione conjugation

Question 3

what phase 2 reaction do nucleophilic xenobiotics undergo

Answer 3

glucuronidation
CoA conjugation
Sulfonation
AA conjugation
Methylation
Acetylation

Question 4

what does the synthesis of glutathione need

Answer 4

required energy

Question 5

what is GSH

Answer 5

glutathione

Question 6

what family is glutathione in

Answer 6

glutathione s-transferase (GST)

Question 7

what type of reaction does glutathione conjugation start

Answer 7

reduction

Question 8

describe glutathione conjugation reducing capacity in the cell

Answer 8

• can reduce ROS

-

Question 9

what regenerates glutathione

Answer 9

glutathione reductase (GSSG=2GSH)

Question 10

what are the xenobiotic substrates of glutathione conjugation

Answer 10

• electrophile

- electrophilic C or heteroatom (O,N,S)

Question 11

what are the three common characteristics of substrates for glutathione conjjgation

Answer 11

1. hydrophobic
2. contain an electrophilic atom
3. react nonenzymatically with GSH at some measurable rate

Question 12

why do electrophiles need to be detoxed

Answer 12

electrophiles are potentially toxic by binding to critical nucleophiles (proteins, nucleic acids)

Question 13

all biotransforming enzymes have the potential to create what

Answer 13

reactive intermediates

Question 14

what conjugation enzyme family is glucuronidation in

Answer 14

UDP-glucuronosyltransferase (UGT)

Question 15

where is glucuronidation located

Answer 15

lumen of the ER (liver, kidney,GI,lung,skin,brain,spleen)

Question 16

what families are the major xenobiotic metabolizing UGTs

Answer 16

UGT1 UGT2

Question 17

what are the substrates for glucuronidation

Answer 17

• 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)

Question 18

examples of glucuronidation substrates

Answer 18

propofol, acetaminophen, morphine, carbamazepine

Question 19

purpose of glucuronidation detoxification

Answer 19

drug metabolism for excretion
or
activation to a therapeutic metabolite

Question 20

explain influence fasting can have on glucuronidation

Answer 20

fasting decreases the cofactor UDPGA and can predispose to acetaminophen toxicity

Question 21

what induces UGTs

Answer 21

nicotine, cabbage, brussels sproats

Question 22

what enhances glucuronidation of acetaminophen

Answer 22

nicotine, cabbage, brussel sproats

Question 23

what inhibits UGTs

Answer 23

valproic acid inhibits UGTs, increasing plasma AUC for the UGT/glucuronidation targets lorazepam and carbamazepine

Question 24

what is carbamazepine

Answer 24

anticonvulsant

Question 25

describe phase 1 pathway of carbamazepine

Answer 25

1. CBZ induces CYP3A4 | 2. CBZ metabolism hindered by CYP3A4 inhibitors

Question 26

describe phase 2 pathway of carbamazepine

Answer 26

1. CBZ metabolism enhanced by UGT inducers

Question 27

what conjugating enzyme family is sulfation

Answer 27

sulfotransferase (SULT)

Question 28

describe xenobiotic metabolizing SULTs

Answer 28

soluble and located in cytoplasm

Question 29

what are the two main SULT families

Answer 29

SULT1- phenols, catecholamines | SULT2- polycyclic aromatic hydrocarbons

Question 30

what are the substrates of sulfonation

Answer 30

many endogenous and xenobiotics that undergo O-glucuronidation

Question 31

compare sulfation to glucuronidation

Answer 31

sulfation has high affinity, low capacity versus glucuronidation

Question 32

what xenobiotic substrates can be activated to therapeutic metabolite by sulfation

Answer 32

minoxidil, morphine

Question 33

describe inhibition of SULTs

Answer 33

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

Question 34

in what way is acetaminophen biotransformation hindered by ethinyl estradiol

Answer 34

- they compete for SULTs which can send acetaminophen toward glucuronidation or CYP450

Question 35

what induces SULTs

Answer 35

coadministration of rifampin and ethinyl estradiol

Question 36

how does rifampin influence ethynyl estradiol transformation

Answer 36

rifampin can increase the clearance of ethinyl estradiol by 190% which decreases its AUC and plasma concentration