Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Genetics of Complex Disease > Pharmacogenetics > Flashcards

Pharmacogenetics Flashcards

0
Q

how is pharmacogenomics defined?

A

a study of the effect of drugs on gene expression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
1
Q

how is pharmacogenetics defined?

A

the study of inherited genetic variation to drug response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

what are three examples of polymorphisms?

A

minisatellites, microsatellites and SNPs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

what is a minisatellite?

A

tandem repeats of 14-100 base pairs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

what are microsatellites?

A

short sequences of tandem repeats of 2-5 base pairs, e.g. CA repeats

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

what are variable number tandem repeats (VNTRs)?

A

variable numbers of minisatellite and microsatellite repeats

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

give three consequences of polymorphisms in drug responses

A

alterations to toxicity, efficacy and disease susceptibility

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

what effect can polymorphisms have on drug toxicity?

A

exaggerated effect or effect on inappropriate target

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

which drugs are influenced by the TPMT protein?

A

TPMT influences the metabolism of two anti-cancer drugs: 6-mercaptopurine and azathioprine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

what does TMPT stand for?

A

thiopurine s-methyltransferase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

what is 6-mercaptopurine?

A

a purine antimetabolite prodrug that produces active 6-thioguanine nucleotides that are incorporated into DNA to trigger cell apoptosis

(therefore is used as a chemotherapy drug)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

what is azathioprine?

A

a 6-mercaptopurine prodrug used as an immunosuppressant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

which endogenous body molecule does 6-mercaptopurine closely resemble?

A

hypoxanthine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

what is the action of TPMT on 6-mercaptopurine?

A

TPMT is a methyltansferase enzyme that methylates 6-mercaptopurine to inactivated 6-methylmercaptopurine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

what is the effect of high TPMT activity?

A

increased 6-MP inactivation therefore decreased 6-MP therapeutic effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

what is the result of decreased TPMT activity?

A

increased activity of 6-MP and therefore increased 6-MP therapeutic effect - may potentially induce 6-MP activity in all cells and not just rapidly diving cancerous cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

what polymorphism is associated with low TMPT activity?

A

TMPT*3A null allele

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

why is the TMPT*3A alle associated with decreased TMPT activity?

A

the allele contains two SNPs (Ala154Thr and Tyr240Cys) associated with TMPT protein instability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

which three groups result from varying TMPT activity? why is this?

A

LOW activity = TPMT3A/TPMT3A
MEDIUM activity = TPMT1A/TPMT3A
HIGH activity = TPMT1A/TPMT1A

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

how many caucasians have the TPMT*3A null allele and therefore lack TPMT?

A

1 in 300 (compared to 1 in 2500 asians)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

how do TPMT*3A homozygotes fare when given 6-mercaptopurine?

A

due to low levels/absent TPMT, they experience high thiopurine toxicity (due to high levels of 6-MP and therefore 6-thioguanine nucleotides) and may experience life-threatening myelosuppression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

what is myelosuppression?

A

bone marrow suppression - i.e. a decrease in leukocytes, erythrocytes and thrombocytes
(is a serious side effect of chemotherapy)

22
Q

how do TMPT1A/TMPT1A homozygotes fare when given 6-mercaptopurine?

A

high TPMT activity results in increased 6-MP metabolism and decreased therapeutic effect

23
Q

is TPMT gene testing currently carried out before treatment with 6-mercaptopurine?

A

yes, in 2003 the FDA recommended TPMT testing and dosing recommendations for 6-MP

24
what effect can polymorphisms have on drug efficacy?
polymorphisms can create unresponsive drug targets, stop the activation of a prodrug or induce too rapid metabolism/excretion of the drug
25
what is the cytochrome P450 family of enzymes?
a multigene family of enzymes that oxidise drugs and other foreign compounds, highly expressed in the liver
26
what is a debrisoquine?
an antihypertensive drug
27
which enzyme metabolises debrisoquine?
the cytochrome P450 enzyme CYP2D6
28
how many CYP2D6 polymorphisms have now been identified?
>70
29
what are four common CYP2D6 polymorphisms?
``` CYP2D6*3 = base (A) deletion CYP2D6*4 = altered splice site CYP2D6*5 = entire CYP2D6 gene deletion ```
30
what two types of metabolism are related to CYP2D6 metabolism?
"poor metabolisers" and "ultrarapid metabolisers"
31
what are "poor metabolisers" with relation to cytochrome P450 enzymes?
individuals who poorly metabolise drugs oxidised by the CYP2D6 enzyme due to a recessive trait requiring the inheritance of two defective CYP2D6 gene copes
32
what are "ultrarapid metabolisers" with relation to cytochrome P450 enzymes?
individuals that demonstrate high metabolism of drugs oxidised by CYP2D6 due to extra copies (between 2 and 13 copies possible) of the CYP2D6 gene adjacent to the wt CYP2D6 and therefore increased levels of CYP2D6
33
how do CYP2D6 polymorphisms influence metabolism of nortryptyline?
1 CYP2D6 gene copy = high [nortryptyline] and therefore high therapeutic efficacy (though may get drug toxicity) 13 CYP2D6 gene copies = low [nortryptyline] and therefore very low therapeutic efficacy
34
how do poor metabolisers of CYP2D6-metabolised drugs fare when given these drugs?
decreased metabolism of drugs results in high drug levels and an increased risk for an adverse drug reaction OR if the drug is a prodrug requiring metabolic activation by CYP2D6 then the drug will have no therapeutic effect
35
how do ultrarapid metabolisers of CYP2D6-metabolised drugs fare when given these drugs?
very high drug metabolism results in decreased therapeutic effect of drugs at normal drug dose
36
is CYP2D6 gene testing currently carried out before treatment with CYP2D6-metabolised drugs?
no, as few studies have shown a clear benefit of CYP2D6 genotyping in a clinical setting
37
what effect can polymorphisms have on disease susceptibility with relation to drugs?
the existence of polymorphisms in many drug targets, bio transforming enzymes or transporters may effect susceptibility to disease
38
what is MDR1?
an ATP-dependent efflux pump (of the ATP-binding cassette ABC transporter family) with broad substrate specificity, expressed in the colon, liver, kidney and blood brain barrier
39
what common MDR1 polymorphism is associated with inflammatory bowel disease?
an Ala893 variant
40
why is the Ala893 variant in MDR1 associated with inflammatory bowel disease?
the Ala839 variant is associated with decreased MDR1 activity when compared to the 839Ser variant, resulting in decreased removal of harmful substances and therefore increased risk of IBD
41
when are you likely to see an adverse drug reaction?
when the drug has a narrow therapeutic window or when the drug is metabolised by a single enzyme pathway (i.e. there is a lack of redundancy)
42
an adverse drug reaction to which drug can clinically resemble primary biliary cirrhosis?
augmentin
43
what is augmentin?
i.e. amoxicillin/clavulanic acid or co-amoxiclav = an antibiotic useful in the treatment of bacterial infections
44
what are the adverse toxic effects associated with augmentin?
hepatotoxicity - reversible cholestatic jaundice with lymphocyte infiltrates and immune damage to interlobular bile ducts
45
an adverse drug reaction to augmentin is often fatal: true or false?
false - an adverse drug reaction to augmentin is rarely fatal
46
what is thought to occur in patients with a genetic predisposition to an adverse drug reaction to augmentin?
they develop an immune-allergic reaction to augmentin, possibly due to the production of a novel metabolite with structural similarity to a self-antigen
47
what are the 3 major drug-induced causes of liver toxicity?
augmentin, diclofenac and flucloxacillin
48
what is flucloxacillin?
an antibiotic used in the treatment of staphylococcus infections
49
what adverse drug reaction is associated with flucloxacillin?
cholestatic hepatitis (and therefore jaundice)
50
1 in ___ cases of flucloxacillin are fatal without a liver transplant
20
51
what is the primary risk allele associated with susceptibility to flucloxacillin drug-induced liver injury (DILI)?
the HLA*B5701 allele
52
there is an ___-fold increased risk of flucloxacillin drug-induced liver injury if an individual has the HLA-_____ risk allele
there is a 80-fold increased risk of flucloxacillin drug-induced liver injury if an individual has the HLA-B*5701 risk allele
53
the HLA-B*5701 is also a risk allele for an adverse drug reaction to which drug?
abacavir, a HIV-1 antiviral

Genetics of Complex Disease (6 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions