ABC And SLCO Transporters

Question 1

What are the 3 most common polymorphisms in ABCB1 gene

Answer 1

Exon 12 : silent
Exon 21: substitution
Exon 26 : silent

Question 2

What are the 3 common haplotypes for ABCB1 gene

Answer 2

TTC
CGT
CGC

Question 3

What effects do ABCB1 haplotypes have on fluvastatin, pravastatin, lovastatin and rosuvastatin

Answer 3

No sig effect

Question 4

Does MDR1 polymorphisms have an effect of MDR1 transport activities

Answer 4

No effect

Question 5

What are the 2 MDR1 polymorphisms

Answer 5

G2677T/A
C3435T

Question 6

What are the potential effects of ABCB1 gene polymorphisms

Answer 6

Changes to mRNA and protein expression/ stability

Changes to transport activity and substrate specificity

Reduced transport capacity = reduced drug efflux

Question 7

Describe ABCG2

Answer 7

Transporter deleted in breast cancer cell line

Important function is in drug absorption and biliary excretion

Physiological role in uric acid excretion

Question 8

What is the allele frequency of variant 421C>A in ABCG2

Answer 8

High allele frequency

Asians: 36%
Europeans: 12%
Africans: 2.3%

Question 9

What is the result of variant 421C>A

Answer 9

Amino acid change
Gln141Lys

Question 10

What is the effect of variant 421C>A

Answer 10

Impaired protein folding and cellular processing
Protein expressions in membrane reduced by 30/40%
Reduced transport in vivo by 20%

Question 11

What affect does variant 421C>A have on BCRP protein conc

Answer 11

Lower protein conc

Question 12

What is the effect of ABCG2 on rosuvastatin pharmacokinetics

Answer 12

Cmax and AUC sig higher in A/A compared to C/C

Higher conc may increase risk of muscle toxicity

Question 13

What is the role of SLCO1B1 gene

Answer 13

Encodes OAT1B1 -> transports anionic drugs into liver
Recuse systemic availability

Question 14

What SLCO1B1 polymorphism leads to decreased transport in OATP1B1 and what is its effect

Answer 14

*5 = Val174Ala

3-fold lower Vmax

Question 15

What SLCO1B1 polymorphism leads to increased transport in OATP1B1

Answer 15

*14
*20

Rare amino acid substitutions

Question 16

What SLCO1B1 polymorphism leads to gain of function in OATP1B1

Answer 16

*14
*20

Highly increased: homozygous (AA), (CC)
Increased: heterozygous (AC)

Question 17

What SLCO1B1 polymorphism leads to loss of function in OATP1B1

Answer 17

*5

Decreased = heterozygous (TC)
Poor = homozygous (CC)

Question 18

How are transporter polymorphism relevant to statins

Answer 18

SLCO1B1 = relevant to many statins
ABCG2 = use of rosuvastatin only

Question 19

Describe G6PDH

Answer 19

Required to produce GSH

Question 20

Describe G6PDH deficiency

Answer 20

More common in males (located on X chromosome)
14 exon gene

Common in African or Mediterranean origin

Question 21

How are the severity of G6PDH variants classes

Answer 21

Class I = most severe
Class V = mild

Based on residual enzyme activity

Question 22

What are some compounds associated with drug induced haemolysis

Answer 22

Nitrofurantoin
Primaquine
Sulphamethoxazole
Acetanilide
Napthalene

Question 23

Name the Mediterranean G6PDH variant

Answer 23

Gly163Ser

Question 24

Name the Vianchchan G6PDH variant

Answer 24

Val291Met

Question 25

What class are the Vanua Lava and Viangchan variants

Answer 25

Class II