Genomic Medicine Lecture

Question 1

Polymorphism

Answer 1

Mutation that is present in a certain proportion of the population

Question 2

Single nucleotide polymorphism (SNP)

Answer 2

Variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree.

Question 3

Pharmacogenomics

Answer 3

influence of variations in DNA sequences on the effect of drugs, plays a role as genomic sequencing data becomes increasingly available. Searching through the entire genome for new drug targets.

Question 4

Pharmacogenetics

Answer 4

Study of the role of inheritance in individual variation in drug metabolism phenotypes. What genes are involved in pharmacokinetics of a drug?

Pharmacogenetics is not a new concept: Example- 1940s, Increased frequency of hemolytic anemia in African American soldiers treated with primaquine- G6PDH. 1977-CYP2D6 polymorphism linked to altered pharmacokinetics and pharmacodynamics

Question 5

Drug Metabolism: Dominant Role of Cytochrome P450 enzymes

Answer 5

Common family of enzymes to metabolize drugs

Broad substrate specificities

CYPs

Superfamily of membrane-bound proteins

Highest activities in liver

Key enzymes for drug metabolism are: CYP3A4, CYP2D6, CYP2C19, CYP2C9

Question 6

CYP2D6

Answer 6

Debrisoquine is Metabolized by CYP2D6, a Polymorphic Enzyme

CYP2D6 controls clearance of ~20% of drugs

CYP2D6 is highly polymorphic (nearly 100 human variants reported)

Most variants show diminished or no activity

CYP2D6 duplication/amplification also observed

The more CYP2D6= more rapid drug clearance

3 Groups:

Most humans are Extensive Metabolizers

A small percentage are Poor Metabolizers

The smallest group are Ultra Rapid Metabolizers

Distribution among these three groups varies with race and ethnicity

Human CYP2D6 Variants:

Most variants diminish activity

Basis for Poor Metabolizers

Gene duplication responsible for Ultra Rapid Metabolizers

CYP2D6 genotyping currently is in use

Question 7

Discuss the relationship between ethnicity and drug response.

Race/Ethnicity as a surrogate for genetics

Answer 7

As society progresses, race and ethnicity will no longer be indicative of polymorphism and genotype of an individual. Example studied Brazilian populations of individuals born in different areas and the distribution spread to all areas.

CYP2D6 PMs

~ 5 to 10 % of Whites

~ 3 % of Asians and Blacks

CYP2C9 PMs

~ 15 to 25% of Whites

~ 1-5 % of Asians and Blacks

NAT2 Slow metabolizers

~ 50% of Whites and Blacks

~ 80% of Asians and Native Americans

Question 8

Explain how drug-drug interactions can alter the genotype-phenotype relationship.

Answer 8

Drug-Drug Interactions:

Drug Metabolizing Enzymes may be inhibited:

Terfenadine (Seldane®) requires activation by CYP3A4 oxidation to yield Fexofenadine (Allegra®)

Erythromycin and many other drugs compete for/inhibit CYP3A4- Inhibits Terfenadine

Inhibition of metabolism or excretion may require dosing alteration beyond what genotype alone predicts or choice of a different drug to achieve therapeutic concentrations

Question 9

Explain how drug-diet interactions can alter the genotype-phenotype relationship.

Answer 9

Drug-Diet Interactions:

Induction by changes in diet or other exposures increases enzyme expression levels

Increased expression of drug metabolizing enzymes results in lower concentrations and faster elimination of drugs

Following induction, dosing may need to be increased beyond what genotype alone predicts to achieve therapeutic concentrations of drug

Phenacetin example: Tested drug clearing of patients eating bland hospital diet. Fed charcoal coated, smoke meats and tested drug clearance again. Peak drug concentration is much lower, chemicals from charcoal bind nuclear receptors, inducing transcription of these drug clearance enzymes, drug cleared much faster due.

Question 10

Restriction Fragment Length Polymorphism

Answer 10

DNA cut into small pieces by DNA Restriction enzymes to create restriction fragments. Separated by lengths and analyzed by gel electrophoresis.

Question 11

Goals of Pharmacotherapy

Answer 11

Right drug, Right dose, Right patient- achieve predictable outcomes

Question 12

Pharmacokinetics

Answer 12

What the patient does to the drug. Describes the processes which determine these parameters. How much drug gets to target, how quickly it disappears. Distribution out of the blood.

To be effective, a drug or toxicant must: Reach its target(s), In an active form, At a sufficient concentration, For a sufficient period of time.

Getting the right form to the right place in the right amount balances: Absorption, Distribution, Metabolism, Excretion

Question 13

Pharmacodynamics

Answer 13

What the drug does to the patient. Includes adverse effects. Why drugs are prescribed.

Question 14

Genetic variations affecting pharmacokinetics or pharmacodynamics impact on drug choice and do

Answer 14

How do we determine right patient?

Understand applications of genetic analysis to these questions

Appreciate the additional modulation of genetic potential by environmental factors

Question 15

Biomarkers in Drug Labels:

Answer 15

About 160 pharmacogenomic issues listed

74 issues based on drug metabolizing enzymes

Many based on CYP polymorphisms

• CYP2C9 4 entries
• CYP2C19 16 entries
• CYP2D6 39 entries

Other entries for UGT1A1(5 entries),TPMT (3 entries) and NAT1/2 (2 entries)

Question 16

Describe the genetic factors that might influence responses to drugs.

Answer 16

age, gender, coexisting disease, genetics

Pharmacogenetics:

Fast or slow acetlyation

Pseudocholinesterase or butyrylcholinesterase (inability to hydrolyze succinylcholine)

Diversity of cytochrome P450 enzyme system-Forms of enzymes that clear drugs

Question 17

Phase I Enzymes

Answer 17

Modification. (Oxidation, Reduction, Hydrolysis)

Question 18

Phase II Enzymes

Answer 18

Conjugation. (Acetlyation, Glucoronidation, Sulfation, Methylation)