pharmacogenomics

Question 1

What is the function of TPMT?

Answer 1

catalyzes S-methylation of 6-MP mercaptopurine and its prodrug azathioprine (AZA); 6-MP is toxic

Question 2

WHat diseases is azathioprine used for?

Answer 2

purine analog; maintenance therapy in children with ALL; IBD; transplant;

Question 3

What pathways metabolize 6-MP?

Answer 3

TPMT–>6 methyl MP
xanthine oxidase–> 6 thiouric acid
HPRT–> 6 thioguanine nucleotides

Question 4

6 MP toxicity:

Answer 4

hematopoietic toxicity; severity is largely attributable to functional polymorphic variants of TPMT

Question 5

what is the distribution of erythrocyte TPMT activity?

Answer 5

trimodal: 89% high activity; 11% int activity; 0.3 percent very low/no activity

Question 6

What are the major TPMT alleles that account for deficiency?

Answer 6

TPMT *2, *3A, *3C coding polymorphisms; polymorphisms in the promoter region can also affect levels but this is modest in comparison

Question 7

What is the clinical impact of TPMT deficiency?

Answer 7

TPMT deficiency is a good predictors of needing to reduce AZA dose over time; 65% of het/homo patients were intolerant of dose; more patients develop AML 2ndary to 6MP therapy for ALL; increased brain tumor incidence

Question 8

What is the function of DPD?

Answer 8

catalyzes the initial RLS in catabolism of pyrimidines such as T, U, and 5-FU (drug); deficiency is accompanied by pyrimidinemia and uria

Question 9

What is 5FU used for?

Answer 9

treatment of breast/colorectal/other cancers

Question 10

What are signs of DPD deficiency in 5-FU treated patients?

Answer 10

diarrhea, myelosuppression, neuro symptoms

Question 11

What is the prevalence of DPD deficiency?

Answer 11

3% of population are carriers; 1 in 1k are homozygous; autosomal recessive

Question 12

Any use for DPD inactivation?

Answer 12

yes, to increase response to 5-FU therapy; preventing 5FU metabolism