Genetics of ABC and SLCO drug transporters

Question 1

How many introns and exons are in the ABCB1 gene normally and what does it encode for

Answer 1

28, 28
P-glycoprotien

Question 2

what are the three most common polymorphims of the ABCB1 gene

Answer 2

Exon 12: Silent C1236T
Exon 21: Ala393Ser G2677T/A
Exon 26: Silent C3435T

Question 3

what are the three most common haplotypes of ABCB1 gene

Answer 3

TTC
CGT
CGC

Question 4

what is the overall proposed effecr of allele varients for the ABCB1 gene

Answer 4

• that some variants result in reduced transport capacity and thus reduced drug efflux
• this is either by changes to mRNA and protein expression and stability or by changes to transport activity and substrate specificity

Question 5

what gene is responsible for the significant difference between haplotypes for the response of simvastatin

Answer 5

ABCB1

Question 6

which haplotype of ABCB1 causes an significant increase in AUC when simvastatin is administered

Answer 6

TTT

Question 7

what two measurement are increased if a person who possesses the TTT haplotype receives atorvastatin compared to a person with CGC haplotype

Answer 7

T1/2 and AUG

Question 8

which ABCB1 polymorphisms cause a significant decrease in total cholesterol and LDL cholesterol

Answer 8

1236 C>T
2677 G>A/T

Question 9

The presence of which genotype in all three ABCB1 polymorphisms __ the risk of SAMS almost twofold

Answer 9

TT
increased

Question 10

what does SAMS

Answer 10

statin associated muscle syndrome = myalgia

Question 11

true or false - Differences of ABCB1 haplotypes has a significant effect on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.

Answer 11

false

Question 12

true or false - Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities.

Answer 12

true

Question 13

what does the ABCG2 do

Answer 13

drug absorption and biliary excretion
physiological role in uric acid excretion
Normally limits drug absorption

Question 14

what is the most frequent ABCG2 polymorphisms

Answer 14

421 C>A

Question 15

what is the allele frequency of the ethnicity’s for ABCG2 (421 C>A)

Answer 15

Asians - 29-36%
Europeans - 4.5-12%
African - 0-2.3%

Question 16

whats is the Amino acid change of ABCG2 (421C>A) and what is the risk factor associated

Answer 16

Gln141Lys, Risk factor for gout

Question 17

what is the effect of ABCG2 421C>A on the protien

Answer 17

• Impaired protein folding and cellular processing
• Protein expression in the cell membrane reduced by 30-40%
• Reduced transport activity (by >20% in vivo)
  -> Reduced efflux and increased drug absorption

Question 18

what is the effect of the ABCG2 polymorphim on Rosuvastatin

Answer 18

• Normal pumps a large proportion of the drug back into the lumen of the small intestines
• Individuals with the polymorphism will have lower BCRP protein conc
• Cmax and area under the curve (AUC) significantly higher in A/A compared to C/C

Question 19

what does high concentration of Rosuvastatin cause in the body

Answer 19

increases the risk of muscle toxicity

Question 20

what does the SLCO1B1 gene encode

Answer 20

organic anion transporter 1B1
-especially hydrophilic compounds, into liver reducing systemic availability

Question 21

what is the effect of SLCO1B1*5

Answer 21

lead to decreased transport
Val174Ala
has 3-fold lower Vmax

Question 22

what two amino acid substitutions increases transport activity in SLCO1B1

Answer 22

*14 = Pro155Thr -(C463A)
*20 = Leu643Phe (A1929C)

Question 23

What is effect of SLCO1B1*5 on pravastatin

Answer 23

• CC haplotype (variant) causes a higher plasma concentration of pravastatin

Question 24

If were were using genotype to predict OATPC function, who would have highly increased function ?

Answer 24

Homozygous for either *14 or *20

Question 25

If were were using genotype to predict OATPC function, who would have increased function ?

Answer 25

heterozygous for either *14 or *20

Question 26

If were were using genotype to predict OATPC function, who would have decreased function?

Answer 26

Heterozygous for *5

Question 27

If were were using genotype to predict OATPC function, who would have decreased function?

Answer 27

Homozygous for *5

Question 28

what is nessacary to produce Glutathione

Answer 28

Glucose-6-phosphate dehydrogenase

Question 29

If GSH is limiting due to low G6PDH and lack of NADPH what happens

Answer 29

haemolytic anaemia can result due to low levels of GSH in erythrocytes

Question 30

what is the genetic reason for G6PDH deficiency

Answer 30

Over 230 mutations in the 14 exon gene located on X chromosome
- reduced protein function

Question 31

who is the most at risk to G6PDH deficiency

Answer 31

Men because its X linked
Heterogenous female still produce enough functional proteins
Homozygous females are rare

Question 32

Exposure to what (e.g. __) may trigger haemolytic anaemia

Answer 32

• drug or other pro-oxidant xenobiotic
• fava beans

Question 33

what are the amino acid changes responsible for G6PDH variant

Answer 33

• A = Asp142Asn & Val68Met
• Mahidol = Gly163Ser
• Mediterranean = Ser188Phe
• Vanua Lava = Leu128Pro
• Viangchan = Val291Met

Question 34

what compounds are associated with drug induced haemolysis

Answer 34

Nitrofurantoin
Primaquine
Sulphamethoxazole
Acetanilide
Naphthalene