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TOX 4000 Medical Toxicology > Phase 2 biotransformation > Flashcards

Phase 2 biotransformation Flashcards

1
Q

what does phase 2 lead to

A

large increase in hydrophilicity and excretion

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2
Q

what phase 2 reaction do electrophilic xenobiotics undergo

A

glutathione conjugation

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3
Q

what phase 2 reaction do nucleophilic xenobiotics undergo

A 
glucuronidation
CoA conjugation
Sulfonation
AA conjugation
Methylation
Acetylation
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4
Q

what does the synthesis of glutathione need

A

required energy

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5
Q

what is GSH

A

glutathione

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6
Q

what family is glutathione in

A

glutathione s-transferase (GST)

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7
Q

what type of reaction does glutathione conjugation start

A

reduction

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8
Q

describe glutathione conjugation reducing capacity in the cell

A
  • can reduce ROS

-

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9
Q

what regenerates glutathione

A

glutathione reductase (GSSG=2GSH)

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10
Q

what are the xenobiotic substrates of glutathione conjugation

A
  • electrophile

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

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11
Q

what are the three common characteristics of substrates for glutathione conjjgation

A
  1. hydrophobic
  2. contain an electrophilic atom
  3. react nonenzymatically with GSH at some measurable rate
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12
Q

why do electrophiles need to be detoxed

A

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

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13
Q

all biotransforming enzymes have the potential to create what

A

reactive intermediates

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14
Q

what conjugation enzyme family is glucuronidation in

A

UDP-glucuronosyltransferase (UGT)

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15
Q

where is glucuronidation located

A

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

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16
Q

what families are the major xenobiotic metabolizing UGTs

A

UGT1 UGT2

17
Q

what are the substrates for glucuronidation

A
  • 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)
18
Q

examples of glucuronidation substrates

A

propofol, acetaminophen, morphine, carbamazepine

19
Q

purpose of glucuronidation detoxification

A

drug metabolism for excretion
or
activation to a therapeutic metabolite

20
Q

explain influence fasting can have on glucuronidation

A

fasting decreases the cofactor UDPGA and can predispose to acetaminophen toxicity

21
Q

what induces UGTs

A

nicotine, cabbage, brussels sproats

22
Q

what enhances glucuronidation of acetaminophen

A

nicotine, cabbage, brussel sproats

23
Q

what inhibits UGTs

A

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

24
Q

what is carbamazepine

A

anticonvulsant

25
Q

describe phase 1 pathway of carbamazepine

A
  1. CBZ induces CYP3A4

2. CBZ metabolism hindered by CYP3A4 inhibitors

26
Q

describe phase 2 pathway of carbamazepine

A
  1. CBZ metabolism enhanced by UGT inducers
27
Q

what conjugating enzyme family is sulfation

A

sulfotransferase (SULT)

28
Q

describe xenobiotic metabolizing SULTs

A

soluble and located in cytoplasm

29
Q

what are the two main SULT families

A

SULT1- phenols, catecholamines

SULT2- polycyclic aromatic hydrocarbons

30
Q

what are the substrates of sulfonation

A

many endogenous and xenobiotics that undergo O-glucuronidation

31
Q

compare sulfation to glucuronidation

A

sulfation has high affinity, low capacity versus glucuronidation

32
Q

what xenobiotic substrates can be activated to therapeutic metabolite by sulfation

A

minoxidil, morphine

33
Q

describe inhibition of SULTs

A

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

34
Q

in what way is acetaminophen biotransformation hindered by ethinyl estradiol

A
  • they compete for SULTs which can send acetaminophen toward glucuronidation or CYP450
35
Q

what induces SULTs

A

coadministration of rifampin and ethinyl estradiol

36
Q

how does rifampin influence ethynyl estradiol transformation

A

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

TOX 4000 Medical Toxicology (6 decks)

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