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Biomedical Lab III > Lab 5 > Flashcards

Lab 5 Flashcards

1
Q

What is the purpose of the phase 1 reactions of metabolism?

A

to introduce or unmask functional groups on a molecule.
the purpose is to introduce polarity for excretion (via the kidneys) AND/OR to form conjugates via phase II reactions

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2
Q

what are the type(s) of enzymes in phase 1 metabolism reactions?

A

oxidoreductases and hydrolases

major oxidoreductase enzyme system = p450 monooxygenases (CYP enzymes)

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3
Q

the major _______ system is the CYP enzymes (_____)

A

the major OXIDOREDUCTASE system is the CYP enzymes (P450 MONOOXYGENASES)

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4
Q

what do hydrolases do?

A

they hydrolyze esters, amides, epoxides, and glucuronides

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5
Q

phase 1 reactions convert __ into ____

A

lipophilic molecules into more hydrophilic molecules

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6
Q

as mentioned, the drug-metabolism phase 1 reactions introduce or unmask a polar functional group.

give 4 examples

A

-OH, -NH2, -COOH, -SH

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7
Q

how do the phase 1 metabolism reactions affect pharmacological activity?

A

can increase, decrease, or leave the pharmacological activity unaltered

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8
Q

where are the cytochrome P-450 enzymes located?

A

in the endoplasmic reticulum of hepatic (liver) cells

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9
Q

what is the most frequently used enzyme?

A

cytochromeP450

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10
Q

when are phase 1 metabolism reactions not necessary?

A

if the drug molecule already contains (polar) functional groups that are suitable for conjugation

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11
Q

as mentioned, phase 1 metabolism reactions are not always necessary.
give a specific example of this

A

morphine has 2 hydroxyl groups.

Glucuronic acid oxidation of EITHER (or both) is sufficient for excretion.
phase 1 is not needed

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12
Q

give the chemical formula for phase 1 of drug metabolism reactions

A

Drug + O2 + 2NADPH + H+ —–>(P-450) Drug-OH + H2O + 2NADP+

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13
Q

Phase 2 metabolism reactions consist of what kind of reactions?

A

conjugation reactions. Primarily detoxification reactions

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14
Q

Phase 2 reactions generally do what?

A

convert drugs and their metabolites to more polar PRODUCTS for kidney excretion

Glucuronic acid and glutathione form POLAR PRODUCTS

Methylation terminates pharmacological activity

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15
Q

true or false

phase 1 reactions always proceed phase 2 reactions

A

FALSE

phase 1 is not necessary if a drug molecule already contains functional groups suitable for conjugation (in the case of morphine – glucuronic acid conjugation of either of its 2 hydroxyl groups is suitable for excretion)

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16
Q

_______metabolism primarily undergoes acetylation

A

isoniazid

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17
Q

is acetylation a phase 1 or phase 2 reaction?

A

phase 2

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18
Q

what affects the rate of acetylation?

A

genetic polymorphism

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19
Q

genetic polymorphism affects the rate of acetylation.
slow acetylators are prone to what?

A

drug toxicity

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20
Q

explain how administration of isoniazid can lead to drug toxicity

A

phase 1–
when isoniazid undergoes p450 oxidation, it results in a toxic metabolite that is DETOXIFIED by glutathione (GSH) conjugation (phase 2)

Glutathione depletion and drug toxicity can occur when isoniazid is administered at the same time as other drugs that follow the same metabolic pathway and consume glutathione (acetaminophen, sulfamethoxazole, procainamide)

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21
Q

isoniazid cannot be administered with which drugs? why?

A

acetaminophen, sulfamethoxazole, procainamide

the phase 1 metabolite of isoniazid is TOXIC and is detoxified by glutathione conjugation.
these 3 drugs follow the same metabolic pathway and consume glutathione, which can lead to glutathione depletion and drug toxicity

22
Q

conjugation reactions are primarily ____ reactions

A

phase 2 reactions are conjugation reactions - primarily detoxification reactions

23
Q

what are the targets of phase 2 metabolism?

A

-drugs with (polar)functional groups that can participate in conjugation

-phase 1 metabolites that are still lipophilic

24
Q

what are the enzymes involved in PHASE 2 metabolism?

A

TRANSFERASES (involve the transfer of a suitable moeity)

-N-acetyltransferase (for acetylation)
-glutathione transferase (for glutathione conjugation)

(glucuronic acid enzyme?0

25
Q

explain what the cytochrome p450 enzymes are

A

a SUPERFAMILY of mono-oxygenases that catalyze the formation of newly hydrophilic groups such as hydroxyl, amine, or sulfhydryl group on the substrate (drug)

26
Q

name 2 places where cytochrome p450 enzymes are found

A

PRIMARILY in the membranes of the endoplasmic reticulum (microsomes) within liver cells

to a lesser extent - in other tissues such as the intestines, kidneys, and lung cells

27
Q

summarize the reaction that occurs in the cytochrome p450 system

A

Drug-H +O2 +2e- —> Drug-OH + H2O

Drug-OH = oxidized product
Drug-H = substrate

28
Q

Explain the properties of cytochrome isoforms

A

they are expressed by DIFFERENT GENES but have a spectrophotometric absorption peak at or near 450nm when bound and reduced by carbon monoxide.

they have gene similarity or homology (similar protein or nucleic acid sequence)

29
Q

explain how each cytochrome isoform is named

A

each uses CYP to represent the cytochrome p450 SUPERFAMILY

followed by a number, a letter, and another number(italics)

each indicates the degree of homology (common amino acid sequence)

30
Q

true or false

each cytochrome isoform metabolizes the same substrates

A

FALSE – each metabolizes specific substrates

31
Q

Why are mammalian CYP enzymes important?

A

for endogenous metabolism and exogenous metabolism

endogenous - steroid hormones, vitamin D,

exogenous - drugs and xenobiotics

32
Q

what is a key predictor of drug responsiveness and toxicity?

A

either expression of the enzyme or alteration in its activity

33
Q

how can p450 enzymes be induced or inhibited?

A

through drugs and some food

34
Q

as mentioned, drugs and some food can induce/inhibit p450 enzymes.
what can these drug interactions do?

A

they can enhance the toxicity of the drug OR reduce the therapeutic effect of another drug

35
Q

give an example of a drug that INHIBITS cyp enzymes and a drug that INDUCES cyp enzymes

A

INDUCER = barbituates. they induce CYP2B which increases the metabolism of drugs, resulting in decreased cost concentration

INHIBITOR = ketoconazole. CYP3A4 inhibitor. REDUCES the metabolism of drugs, resulting in increased drug concentration

36
Q

give an example of a food that affects CYP enzymes

A

grapefruit juice contains a CYP3A4 inhibitor, which reduces the metabolism of drugs (like ketoconazole) which significantly increases the drug concentration of CYP3A4 substrates

37
Q

give 8 examples of drugs that are substrates for CYP3A4.
Thus, their concentration is greatly increased by ketoconazole and grapefruit juice (which contain CYP3A4 inhibitor)

A

tylenol
cyclosporin A
diazepam
erythromycin
lidocaine
lovastatin
taxol
warfarin

38
Q

Genetic variants of cytochrome isoforms are due to what?

A

SNP – a single nucleotide polymorphism
-insertions or deletions of DNA bases

AND

CNVs - copy number variations

39
Q

what largely attributes to the presence of SNPs? (single nucleotide polymorphism)

A

individual and population differences in drug metabolism

40
Q

how is enzyme activity determined?

A

by specific combinations of genetic variants (ALLELES or HAPLOTYPES)

41
Q

knowledge of the haplotype combination is used to classify what?

A

4 different drug metabolizer status types:

  1. Poor metabolizers – little to no enzyme activity
  2. Intermediate metabolizers - decreased enzyme activity
  3. Extensive metabolizers - normal enzyme activity
  4. Ultra rapid metabolizers - increased enzyme activity compared to extensive metabolizers
42
Q

true or false

drugs are metabolized differently by different populations

A

TRUE

in caucasions, the polymorphism for the POOR METABOLIZER phenotype is only seen in 3% of the population as its seen in 20% of the asian population

43
Q

do drug-drug interactions affect drug metabolism in our bodies?

A

yes

when drugs share common pathways, enzymes or cofactors will be depleted which will increase drug levels.

the use of alternate metabolic pathways may then result in the production of TOXIC DRUG METABOLITES

44
Q

When drugs induce enzymes, what happens?

A

increases enzyme isoform synthesis – affecting more than one P450 isoform and INCREASING THE METABOLISM OF OTHER DRUGS TOO

45
Q

give 2 reasons why enzyme inhibition would take place.
what may it cause?

A

enzyme inhibition could be done to increase drug levels or modify/inactivate an enzyme

can cause severe toxicity OR may even be beneficial to reduce the dose and enhance the therapeutic response

46
Q

what transfers electrons from NADPH to the CYP450-substrate(drug) complex?

A

Microsomal NADPH-cytochrome p450 reductase (a flavoprotein)

47
Q

after an electron from NADPH is added (via cytochrome p450-reductase), what happens?

A

protons (delivered from the cofactor NADH or NADPH) are essential to split molecular oxygen and add a single oxygen atom to the substrate

delivered from NADH or NADPH to the active site in the p450 enzyme

48
Q

at the end of the schematic for P450 reactions, the substrate (drug) is _______

A

OXIDIZED

49
Q

Fe3+ to Fe2+

is this reduction or oxidation?

A

reduction - gain of electrons

50
Q
A

Biomedical Lab III (10 decks)

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