Exam 4 - Review Questions

True or False: Warfarin is an antagonist of Vitamin K

True

Regarding Vitamin K and its role, which of the following statements are correct?

A. Vitamin K epoxide reducatase complex subunit 1 converts oxidized form of vitamin K to reduced form.

B. Vitamin K is essential for the maturation of certain coagulation factors

C. Vitamin K is a cofactor for the enzyme g-glutamyl carboxylase

D. Warfarin inhibits VKORC1

E. All of the above

E. All of the above

Vitamin K is important for the maturation of which of the following coagulation factors?

A. Factor II

B. Factor VII

C. Factor IX

D. Factor IX

E. All of the above

E. All of the above

True or False: ADP can cause platelet aggregation whereas Adenosine diphosphatase can prevent platelet aggregation by degrading ADP

True

List hereditary reasons for the development of VTE

Mutations in Factor II and Factor V

Deficiency in protein C and deficiency in anti-thrombin

High levels of factor VIII

What is the co-factor for gamma glutamyl carboxylase enzyme?

A. Vitamin A

B. Vitamin D

C. Vitamin K

D. Vitamin E

C. Vitamin K

Which of the following CYPs are involved in the metabolism of Warfarin?

A. CYP2C9

B. CYP1A

C. CYP3A4

D. All of the above

D. All of the above

Black box warning in prescription drugs is_______

A. It is a type of alert notification that appears on the package insert for certain prescription drugs which notifies patients on the risk associated with taking the drugs due to gene polymorphisms.

B. Alert notification to take the drug after the food in the morning and night

C. Alert notification to indicate that it is only to be given people who are above 20 years old.

D. Alert notification to indicate that it is used in treating animal diseases.

A. It is a type of alert notification that appears on the package insert for certain prescription drugs which notifies patients on the risk associated with taking the drugs due to gene polymorphisms.

Clinically relevant CYP enzyme involved in the metabolism of warfarin is________

A. CYP2D6

B. CYP2C9

C. CYP2C19

D. All of the above

B. CYP2C9

S-Warfarin is metabolized by _____

A. CYP1A

B. CYP3A4

C. CYP2C9

D. All of the above

C. CYP2C9

Define Extensive metabolizer, Intermediate metabolizer, Poor metabolizer and Ultra-metabolizer phenotypes.

Extensive metabolizers: two good copies of the gene (normal)

Intermediate metabolizers: one good copy and one defective copy of the gene

Poor metabolizers: Two defective copy of the gene

Ultra-rapid metabolizers: three or more good copy of the gene

What is the main ADR associated with warfarin in individuals who have CYP2C9*1?

A. Stroke

B. Heart attack

C. Bleeding

D. All of the above

C. Bleeding

C1173T and G1639A alleles for VKORC1 are more common in which of the following populations?

A. Caucasians

B. Asians

C. African Americans

D. All of the above

B. Asians

Which of the following amino acids in the coagulation factors are carboxylated by gammaglutaby carboxylase catalyzed reaction?

A. Alanine

B. Serine

C. Glutamic acid

D. threonine

C. Glutamic acid

True or False: Polymorphisms in CYP2C9 effects warfarin response, but polymorphism in VKORC1 does not.

False

CYP2C9*2 allele is more commonly present in which of the following population?

A. Caucasians

B. Ethiopeans

C. Japanese

D. East Indians

A. Caucasians

True or False: CYP2C9*2 allele is absent or rarely present in Asian population.

True

True or False: In individuals who are homozygous for the CYP2C9*2 or CYP2C9*3 alleles, the enzyme activity will be reduced compared to the individuals who have CYP2C9*1 homozygous alleles

True

In which of the following population, the VKORC1 alleles (C1173T and G1639A) are common?

A. European Americans

B. African Americans

C. Asians

D. A and B

C. Asians

Which is the enzyme in the synthesis of prostaglandins is inhibited by aspirin?

A. Cyclooxygenases-1

B. Lipooxygenase

C. Thromboxane synthase

D. Glutathione S-transferase

A. Cyclooxygenases-1

What is aspirin resistance?

Aspirin resistance is the inability of aspirin to reduce the platelet production of TXA2, and thereby platelet activation and aggregation

Polymorphisms in VKORC1 (C1173T and G1639A) is uncommon in which of the following population?

A. African Americans

B. European Americans

C. Asians

D. All of the above

A. African Americans

Polymorphisms in which of the following genes would affect Plavix therapy?

A. P-glycoprotein (MDR-1)

B. CYP2C19*1

C. P2Y12

D. All of the above

D. All of the above

True or False: CYP2C19*2 and CYP2C19*3 alleles are present in higher frequency in Asian populations than Caucasians.

True

Plavix mechanism of action involves the inhibition of the receptor for which of the following agonists?

A. ADP

B. leukotriens

C. TXA2 (thromboxane A2)

D. Fibrinogen

A. ADP

List any 3 genes among the several which can be genotyped before the commencement of chemotherapy.

There are many…….TPMT (Thiopurine methyl transferase), MTFHR (methylene tetrahydrofolare reductase), DPD (dihydropyrimidine dehydrogenase), CE (carboxylesterase), CYP2D6, thymidylate synthase, etc.

Which of the following are prodrugs and require activation by enzymes?

A. 6 mercatopurine

B. Irinotecan

C. Tamoxifen

D. 5 fluorouracil

E. All of the above

F. A and B

E. All of the above

5’ 10’ methylenetetrahydrofolic acid is a co-factor for which of the following enzyme?

A. Thymidylate synthase

B. TPMT (thiopurine methyl transferase

C. Topoisomerase I and II

D. Telomerase

A. Thymidylate synthase

True or False: The extent of transcription of the UGT1A1 gene is regulated by the number of “TA” repeats in the promoter / 5’ flanking region of the gene.

True

True or False: Arg389 and Se49 alleles of the b1-adrenergic receptor have increased activity (binding to the ligand) and respond better to b1-blockers metaprolol and therefore show greater reduction in blood pressure.

True

ADR observed in response to metoprolol (b-blockers) treatment may depend largely on which of the following gene polymorphisms?

A. CYP2D6

B. b1-adrenergic receptors

C. CYP2C19

D. A and B

E. A, B and C

D. A and B

Dihydropyrimidine dehydrogenase (DPD) enzyme is involved in the metabolism of which of the following anti-cancer drug?

A. 5 Fluorouracil

B. Irinotecan

C. 6-mercaptopurine

D. Tamoxifen

A. 5 Fluorouracil

Myelosuppression is one of the ADR observed in cancer patients treated with 6MP. Which gene polymorphisms is largely responsible to cause this ADR?

A. Glucuronyl transferase (UGT1A1)

B. TPMT

C. Dihydropyrimidine dehydrogenase

D. CYP17

B. TPMT

A 35 year old Asian who was a heavy smoker developed lung cancer. Genotyping showed that he had a mutated EGFR (type 1) and because of this mutation, EGFR was constitutively active. Can Herceptin be effective in this patient?

No

List 2 drugs that can be used to treat the patients described in question number 34.

Erlotinib, Gefitinib, etc.,

Which of the following enzymes convert irinotecan to SN-38, the active metabolite that inhibits cancer growth?

A. Carboxyl esterase

B. UGT1A1

C. CYP3A

D. CYP2D6

A. Carboxyl esterase

Genetic alterations that give rise to non-synonymous SNPs are _______

A. Miss-sense mutation

B. Silent mutations

C. Non-sense mutation

D. None of the above

A. Miss-sense mutation

Which of the following gene polymorphisms would affect treatment of cancer patients with 5-fluorouracil?

A. Dihydropyrimidine dehydrogenase

B. Thymidylate synthase

C. Carboxyl esterase

D. All of the above

E. A and B

E. A and B

Which of the following CYPs can metabolize fluoxetine to norfluoxetine?

A. CYP2D6

B. CYP2C9

C. CYP2C19

D. CYP3A4

E. All of the above

A. CYP2D6

Prozac inhibits the transport of ___________ reuptake in the presynaptic cleft of the neuronal cells.

A. Serotonin

B. Dopamine

C. Norepinephrine

D. All of the above

A. Serotonin

Methylphenidate and amphetamine inhibit________ reuptake in the presynaptic cleft of the neuronal cells.

A. Dopamine

B. Norepinephrine

C. Serotonin

D. A and B

E. A, B and C

D. A and B

Automoxitine inhibits mainly______reuptake in the presynaptic cleft of the neuronal cells.

A. Norepinephrine

B. Serotonin

C. Dopamine

D. Dopamine receptors

A. Norepinephrine

Respiridone is a drug used for the treatment of________

A. Major depressive disorder

B. Minor depression

C. ADHD

D. Schizophrenia

D. Schizophrenia

Which of the following enzyme polymorphism would affect treatment with methylphenidate (for ADHD)?

A. Carboxylesterase I

B. TPMT

C. CYP3A4

D. N-acetyltransferase

A. Carboxylesterase I

Respiridone inhibits which of the following?

A. Serotonin receptor function

B. Dopamine receptor function

C. Norepinephrine receptor function

D. All of the above

E. A and B

D. All of the above

Polymorphisms in which of the following enzyme can affect mercaptopurine metabolism and cause myelo-suppression?

A. TMPT (Thiopurine methyl transferase)

B. Hypoxanthine phosphoribosyl transferase

C. Adenine deaminase

D. DNA polymerase I

E. A and B

A. TMPT (Thiopurine methyl transferase)

Which of the following enzymes are capable of metabolizing/degrading neurotransmitters?

A. COMT (Catechol-O-methyl transferase)

B. Monoamine oxidase

C. Thiopurine methyl transferase

D. UGT1A1

E. A and B

E. A and B

Clozapine is metabolized by which of the following enzyme?

A. CYP1A2

B. CYP2D6

C. CYP2C9

D. CYP2C19

A. CYP1A2

Regarding ADHD, which of the following are correct?

A. It is a developmental disorder, one of the most common psychiatric disorders in the world

B. Symptoms are: inattention, hyperactivity and impulsiveness

C. The most common treatment include treating with methylphenidate and amphetamine

D. Among the children diagnosed to have ADHD, majority are males

E. All of the above

E. All of the above

Which of the following CYPs can metabolize fluoxetine to norfluoxetine?

A. CYP2D6

B. CYP2C9

C. CYP2C19

D. CYP3A4

E. All of the above

A. CYP2D6

Prozac inhibits the transport of ___________ reuptake in the presynaptic cleft of the neuronal cells.

A. Serotonin

B. Dopamine

C. Norepinephrine

D. All of the above

A. Serotonin

Automoxitine inhibits mainly______reuptake in the presynaptic cleft of the neuronal cells.

A. Norepinephrine

B. Serotonin

C. Dopamine

D. Dopamine receptors

A. Norepinephrine

Respiridone is a drug used for the treatment of________

A. Major depressive disorder

B. Minor depression

C. ADHD

D. Schizophrenia

D. Schizophrenia

Which of the following enzyme polymorphism would affect treatment with methyphenidate (for ADHD)?

A. Carboxylesterase I

B. TPMT

C. CYP3A4

D. N-acetyltransferase

A. Carboxylesterase I

Respiridone inhibits which of the following?

A. Serotonin receptor function

B. Dopamine receptor function

C. Norepinephrine receptor function

D. All of the above

E. A and B

D. All of the above

Which of the following enzymes are capable of metabolizing/degrading neurotransmitters?

A. COMT (Catechol-O-methyl transferase)

B. Monoamine oxidase

C. Thiopurine methyl transferase

D. UGT1A1

E. A and B

E. A and B

Clozapine is metabolized by which of the following enzyme?

A. CYP1A2

B. CYP2D6

C. CYP2C9

D. CYP2C19

A. CYP1A2

Regarding ADHD, which of the following are correct?

A. It is a developmental disorder, one of the most common psychiatric disorders in the world

B. Symptoms are inattention, hyperactivity and impulsiveness

C. The most common treatment includes treating with methylphenidate and amphetamine

D. Among the children diagnosed to have ADHD, majority are males

E. All of the above

E. All of the above

Case I:

A 64-year-old Asian American woman with a past medical history of hypertension, hypercholesterolemia received 2 drug-eluting stents 10 days ago for the management of myocardial infarction. Before undergoing coronary intervention, she received a single dose of aspirin (325 mg) and Plavix (600 mg). Her current regimen includes Lipitor 20 mg daily, Plavix 75 mg daily. As a part of clinical trial, platelet function testing was performed today and was found to be a non-responder to Plavix and is at increased risk of ischemic events. What genetic polymorphism may explain why this patient is a non-responder to Plavix?

A. Polymorphisms in CYP2C19

B. Polymorphisms in P2Y12

C. Polymorphisms in p-glycoprotein

D. Polymorphisms in COX-1

E. A, B and C

E. A, B, and C

Case 2:

Two family members who inherited defective (mutated) prothrombin gene from their parents were at high risk of developing venous thromboembolism (VTE). The genotyping revealed that Mr. KC had CYP2C9*1/*1 alleles and the other member had CYP2C9*1/*3 alleles. Based on your understanding in the pharmacogenomics course, what would you recommend with regard to warfarin dosing to prevent VTE?

A. Give the same warfarin dose to both individual

B. Warfarin cannot be given to either of the two individuals

C. The individual with CYP2C9*1/*3 alleles should be given lower dose of warfain (3.32 mg/daily) compared to the individual who has CYP2C9*1/*1 allele (5.63 mg/ day)

D. The individual with CYP2C9*1/*1 alleles should be given lower dose of warfarin (3.32 mg/daily) compared to the individual who has CYP2C9*1/*3 alleles (5.63 mg/ day)

C. The individual with CYP2C9*1/*3 alleles should be given lower dose of warfain (3.32 mg/daily) compared to the individual who has CYP2C9*1/*1 allele (5.63 mg/ day)

Case 3:

Beatrice is a 45 year old Caucasian female. Her mother died of breast cancer shortly after immigrating to the United States from Israel. Beatrice’s older sister, Gertrude, was diagnosed with breast cancer while in her 50s, which was estrogen receptor positive, supporting her as a strong candidate for tamoxifen therapy. However, Gertrude’s cancer did not respond to tamoxifen therapy. Additional chemotherapeutic measures to treat Gertrude’s cancer were not successful.

What hereditary genes are known that may be contributing factors to the development of Beatrice’s breast cancer?

Name a possible pharmacogenomics consideration that may affect the efficacy of tamoxifen therapy.

What hereditary genes are known that may be contributing factors to the development of Beatrice’s breast cancer?

Some examples include: HER2, BRCA!, BRCA2, p53, etc.,,

Name a possible pharmacogenomics consideration that may affect the efficacy of tamoxifen therapy.

Genotype Beatrice for CYP2D6 alleles. Endoxifen is the active metabolite of tomoxifen and is the estrogen receptor antagonist. Endoxifen production from tamoxifen requires CYP2D6*1 allele or CYP2D6*2 allele.

If Beatrice has CYP2D6*3, CYP2D6*4, CYP2D6*5, all these are defective enzymes, and in individuals with these alleles, tamoxifen will not be metabolized to endoxifen. Do not give tamoxifen if Beatrice has 3/4/*5 alleles.

If Beatrice has CYP2D6*9, CYP2D6*10, OR CYP2D6*17 alleles, all these have decreased activity. Tamoxifen can be given but decrease the dose.