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Katzung & Trevor's Pharmacology: Examination & Board Review, 11e >

Chapter 5: Pharmacogenomics

INTRODUCTION
Pharmacogenomics is a rapidly growing area of knowledge regarding the genetic variations that influence
drug metabolism and drug effects. Most of the research in this field to date has involved phase I or phase II
drug metabolism and drug transport. Application of genomic analysis of individual patients to selection of
specific drugs and drug dosage is under investigation.

The inheritance of genetic information via the double DNA helix is now well-understood. The decoding of the
human genome and of many animal and plant genomes has opened a field of research into the molecular
basis of variations between individuals and among populations. The identification of the specific genes (or
groups of genes) that affect drug responses is still incomplete, but knowledge about a small number of these
genes of pharmacologic significance has suggested the possibility that “personalized medicine” is possible
and may become practical in the near future.
Personalized medicine denotes clinical treatment that takes into account the genetic factors that contribute
to disease and the pharmacogenomic factors that influence the response to drug treatment in specific
individuals. Intense academic and commercial research is currently directed at discovering these factors.
Research is also directed at developing accurate and inexpensive tests for pharmacogenetic factors in
individual patients.
As noted in Chapter 4, important genetic variations in drug metabolism exist between individuals.
Furthermore, genetic diseases alter many functions that are drug targets. The identification of specific genes
that control the expression of the molecules involved and the variants (polymorphisms) of those genes has
become the subject of intense research over the last 10–20 years. At present, much data are available
regarding the variants of the genes for some phase I and phase II enzymes and some drug transporters.
Examples of these genetic determinants of drug metabolism and transport are the subject of this chapter.
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High-Yield Terms to Learn

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Pharmacogenetics Synonym for pharmacogenomics; the study of genetic factors that affect drug
responses

Single nucleotide A single base pair substitution in the genome that occurs in >1% of a subject population
polymorphism (cf mutation)
(SNP)

Mutation A polymorphism that occurs in the genome of <1% of a population; more generally, any
change in the genetic material

Allele One of 2 or more alternative forms of a gene. Almost all genes are represented by 2
alleles in the genome (because 22 of the 23 human chromosomes are paired). Allele
variants are denoted “*3,” “*5,” etc

Diplotype Representation of the alleles for a specific gene on both chromosomes of a pair. Thus,
the gene for the enzyme CYP2D6 with allele *3 on one chromosome and *5 on the other
would be denoted CYP2D6*3/*5

Haplotype A series of alleles found in a linked locus on a chromosome

Genotype, Characteristics of the DNA (genotype) and the physiology and biochemistry
phenotype (phenotype) expressed by the DNA of an individual or population

Indels Insertions or deletions of one or more nucleotide bases in genes

Synonymous SNP A single nucleotide variation (SNP) that codes for the same amino acid when read out;
no change of function (phenotype) results

Nonsynonymous An SNP that results in substitution of a different amino acid when read out; a change in
(missense) SNP function may result

Copy number Variation in the number of copies of a gene. An increased number of copies commonly
variation (CNV) results in a gain of function phenotype and vice versa

PM, IM, EM, UM Poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultrarapid
metabolizer, respectively. These terms describe individuals with varying rates of
metabolism of a specific drug or the genomes responsible in such individuals

mtDNA, Y-DNA mtDNA is the DNA found in mitochondria; it is normally inherited only through the
maternal line. Y-DNA is the DNA found in the Y chromosome and is therefore inherited
through the paternal line

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Genome-Wide Analysis of the complete genomes of a population of individuals with regard to the
Association Study frequency of association of specific allelic variations with a specific phenotype
(GWAS)

PHASE I ENZYMES
CYP2D6, CYP2C19, CYP3A4/5, and dihydropyrimidine dehydrogenase are among the drug-metabolizing
enzymes most carefully studied (Table 5–1).

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TABLE 5–1
Polymorphisms associated with altered drug responses.

Alleles or SNPs of
Functional
Major Examples of Drugs Affected
Element
Importance

Phase I enzyme

CYP2C9 *2, *3: decreased Warfarin, phenytoin, antidiabetic sulfonylurea metabolism

function slowed, toxicity increased

CYP2C19 *17: increased Increased or decreased clopidogrel active metabolite

function,
*2, *3: decreased
function

CYP2D6 *1, *2: increased Codeine converted to morphine. Increased function associated
function with increased toxicity; decreased function associated with
*3, *4, *5: decreased analgesia. Increased toxicity of many other drugs
decreased
function

CYP3A4, *1, *8, *11, *13, Metabolism of some dihydropyridines, cyclosporine, tacrolimus
3A5 (SNPs more *16, *17: reduced; increased toxicity
common in 3A5) decreased
function
*3, *5, *6, *7:
decreased
function

Dihydropyrimidine DPYD *2A, *13, Increased toxicity from pyrimidine cancer chemotherapeutic
dehydrogenase rs67376798: agents, eg, 5-FU
(DPD) reduced function

Phase II enzyme

UGT1A1 UGT1A1*28 Increased irinotecan toxicity

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Alleles or SNPs of
Functional
Major Examples of Drugs Affected
Element
Importance

TPMT *2, *3 Increased thiopurine (azathioprine, 6-mercaptopurine, 6-

thioguanine) toxicity

G6PD Mediterranean, Greatly increased susceptibility to hemolysis and other toxicities

Canton, Kaiping: from oxidative stressors but increased resistance to malaria
decreased
function

Transporters

OATP (P-gp, etc) rs4149056: Increased risk of simvastatin myopathy. Many other drugs but
decreased effects inconclusive
function

Receptors

Beta1 ADRB1 Arg389Gly Increased efficacy of metoprolol

adrenoceptor

A. CYP2D6

This enzyme is responsible for the hepatic metabolism of 20% of commonly used drugs. More than 100
polymorphisms of the CYP2D6 gene have been discovered, but only 9 are common. CYP2D6 polymorphisms
are especially important in patients receiving codeine because this enzyme converts codeine to its active
metabolite, morphine. Several deaths due to respiratory depression have been reported in children who
were believed to be ultrarapid metabolizers.

B. CYP2C19

CYP2C19 is responsible for the hepatic metabolism of a small number of very important drugs (clopidogrel,
propranolol, omeprazole, diazepam, and tricyclic antidepressants). Because reduced metabolism of
clopidogrel results in lower concentrations of its active metabolite, reduced function polymorphisms in this
enzyme reduce the efficacy of clopidogrel and increase the risk of clotting in patients with coronary artery
disease. Conversely, gain of function results in increased risk of bleeding. Poor metabolizers and IMs should
receive alternative drugs prasugrel or ticagrelor, not clopidogrel.

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C. CYP3A4 and CYP3A5

CYP3A4/5 are responsible for the metabolism of over 50% of drugs in common use. Some polymorphisms
with important ethnic variability have been described, but relatively few appear to alter pharmacokinetics to
a clinically significant degree.
D. Dihydropyrimidine Dehydrogenase (DPD)

DPD is responsible for the clearance of 5-fluorouracil (5-FU), a first-line prodrug agent for the treatment of
colorectal cancer. Capecitabine and tegafur are oral prodrugs converted in the body to 5-FU. In the body, 5-
FU is converted to cytotoxic 5-fluorouridine 5′-monophosphate (5-FUMP) and 5-fluoro-2′-deoxyuridine-5′-
monophosphate (5-FdUMP) (see Chapter 54). Nonfunctional polymorphisms in the DYPD gene result in
increased toxicity and require reduced dosage.
E. Multiple Enzyme Polymorphisms: CYP2C9 and VCORC1

CYP2C9 and vitamin K epoxide reductase complex subunit 1 (VCORC1) are responsible for the inactivation of
S-warfarin. Some mutations of the VCORC1 gene lead to spontaneous bleeding disorders. Reduced function
polymorphisms in both genes result in increased warfarin action and enhanced risk of bleeding. Algorithms
have been developed to predict the optimal dosage of warfarin, but clinical trials of these algorithms have
not shown improved anticoagulant control thus far.

PHASE II ENZYMES
A. Uridine 5′-diphospho-(UDP) glucuronosyltransferase (UGT1A1)

UGT1A1 is involved in the hepatic excretion of small molecules into the bile. UGT1A1 contributes to the
clearance of SN-38, the bioactive metabolite of irinotecan, a cytotoxic agent used in the treatment of
colorectal cancer. Reduced function polymorphisms result in increased irinotecan-induced bone marrow
depression and diarrhea and require a reduction in dosage.
B. Thiopurine S-methyltransferase (TPMT)

TPMT is important in the inactivation of chemotherapeutic purine derivatives, eg, 6-mercaptopurine (6-MP),
azathioprine, a prodrug of 6-MP, and 6-thioguanine (6-TG). Reduced function polymorphisms result in altered
therapeutic efficacy as well as altered toxicity.

TRANSPORTERS
The organic anion transporter (OATP) 1B1 expressed by the SLCO1B1 gene transports drugs and endogenous
compounds from the blood into hepatocytes. Substrates include statins and methotrexate. Numerous SNPs
are recognized in the SLCO1B1 gene and some are associated with reduced function. Reduced function

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alleles result in elevated concentrations of some statins, especially simvastatin, and increased risk of skeletal
muscle myopathy.
The P-glycoprotein is a very promiscuous transporter found in blood-tissue interfaces. Its former name,
multidrug resistance transporter-1 (MDR1), reflects its importance in expelling cytotoxic drugs from resistant
cancer cells. It is encoded by the ABCB1 gene and over 100 SNPs have been identified in its coding regions.
Association studies with drug pharmacokinetics have yielded mixed results.

HUMAN LEUKOCYTE ANTIGEN (HLA) POLYMORPHISMS

HLA polymorphisms are associated with variations in immunologic responses to drugs, including liver injury,
Stevens-Johnson syndrome, and toxic epidermal necrosis. Examples are given in Table 5–1. Polymorphisms
have been associated with reactions to abacavir, flucloxacillin, allopurinol, and carbamazepine.

SKILL KEEPER: MECHANISM AND TREATMENT OF ACETAMINOPHEN

TOXICITY
A 17-year-old boy is admitted to the emergency department and acetaminophen overdose is suspected (See
Chapter 4). What is the mechanism of acetaminophen toxicity and how is it treated? The Skill Keeper Answer
appears at the end of the chapter.

QUESTIONS
1. A 59-year-old man with acute coronary syndrome is admitted to the hospital for emergency percutaneous
insertion of a coronary stent. Which of the following drugs might cause unexpected results based on the
patient’s CYP2C19 genotype?
(A) Clopidogrel
(B) Codeine
(C) Prasugrel
(D) Ticagrelor
(E) Warfarin
2. A 62-year-old woman with advanced colon cancer is treated with intravenous 5-fluorouracil. Within a few
days, she develops severe diarrhea, and within a week, she shows severe neutropenia. Which of the
following polymorphisms is most likely to be responsible?
(A) CYP2D6*1x3

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(B) CYP2C19*2
(C) CYP2C9*3
(D) DYPD*2A
(E) UGT1A1*28
3. A 38-year-old man is being treated for HIV-induced acquired immunodeficiency syndrome (AIDS). When
abacavir therapy is begun, he develops a severe skin rash. Which of the following pharmacogenomic
diagnoses might explain this skin rash?
(A) CYP2D6*3 (PM)
(B) CYP3A5*3 (PM)
(C) HLA-B*57:01 (EM)
(D) SLCO1B1*5 (PM)
4. A college student volunteers to have his genome decoded as part of a population-wide study of
polymorphisms. He receives a call from the principal investigator informing him that his genome
unexpectedly contains an important single nucleotide polymorphism. Which of the following
polymorphisms is associated with risk of hemolysis and increased resistance to malaria?
(A) CYP2D6*3
(B) CYP2D19*2
(C) TPMT*2
(D) UGT1A1*28
(E) G6PD-(A)–Canton
5. A 7-year-old child is brought to the emergency department in coma with cyanosis. Her mother states that
the girl was given codeine with acetaminophen because of severe bruising a er a fall. Shortly a er the
first dose, the child became unresponsive and “turned blue.” Which of the following alleles might be
responsible for this presentation?
(A) CYP2D6*1x3
(B) CYP2C19*2
(C) CYP2C9*3
(D) DYPD*2A
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(E) UGT1A1*28

ANSWERS
1. Clopidogrel is a prodrug that must be metabolized to an active platelet-inhibiting metabolite by CYP2C19.
Poor metabolizers achieve inadequate platelet inhibition, and EMs and UMs may have excess effect and
bleed. Prasugrel and ticagrelor do not require P450 activation and are not subject to this risk. The answer
is A.
2. CYP2D6*1x3 is a gain-of-function allele and is associated with increased effect and toxicity of codeine.
CYP2C19*2 is a nonfunctional allele associated with reduced efficacy of clopidogrel. CYP2C9*3 with a
reduced function allele of VCORC1 is associated with reduced warfarin clearance. UGT1A1*28 is a reduced
function allele for uridine 5′-diphospho-(UDP) glucuronosyltransferase and enhances irinotecan toxicity.
5-Fluorouracil is cleared by dihydropyrimidine dehydrogenase (DPD). The DYPD*2A allele is
nonfunctional. The answer is D.
3. Poor metabolizers of the CYP2D6*3 genotype are prone to reduced efficacy of codeine. Poor metabolizers
of the CYP3A5*3 type show reduced tacrolimus clearance. Simvastatin toxicity (myopathy) is enhanced in
SLCO1B1 poor metabolizers. Enhanced metabolizers of the HLA-B*57:01 type are prone to abacavir rashes
and flucloxacillin liver damage. The answer is C.
4. CYP2D6 *3 is associated with reduced codeine efficacy. CYP2D19*2 results in reduced clopidogrel
conversion to its active metabolite. TPMT *2 is associated with decreased clearance of 6-mercaptopurine
and increased toxicity. UGT1A1*28 results in decreased clearance and increased toxicity of SN-38, the
active metabolite of irinotecan. G6PD-(A)–Canton is a reduced function allele of the glucose 6-phosphate
dehydrogenase gene that decreases intracellular stores of glutathione, increasing the risk of hemolysis
but reducing susceptibility to malaria. The answer is E.
5. As noted in answer 4, SNPs in CYP2D6 may increase or decrease the efficacy and toxicity of codeine
because the CYP2D6 enzyme is responsible for conversion of codeine to its active metabolite, morphine.
CYP2D6*1xN and *2xN are gain-of-function polymorphisms that result in more efficient conversion to
morphine and increased risk of opioid-induced respiratory depression. The answer is A.

SKILL KEEPER ANSWER: ACETAMINOPHEN TOXICITY AND TREATMENT

In normal dosages, and in individuals with normal liver function, acetaminophen is converted to harmless
glucuronide and sulfate conjugates and is excreted. Overdoses or high therapeutic doses in individuals with
impaired liver function overwhelm the phase II systems and result in intracellular accumulation of a reactive
intermediate that can combine with essential cellular proteins and cause hepatic necrosis. Treatment
attempts to maximize free radical scavenger activity with N-acetylcysteine.

CHECKLIST
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When you complete this chapter, you should be able to:

❑ Name 3 gene polymorphisms that increase or decrease drug efficacy or toxicity.

❑ Name 3 drugs that may require dosage adjustments in specific genetic populations.

❑ Name 1 drug that is more toxic due to a polymorphism.

❑ Name 1 drug that is less effective due to a loss of function polymorphism.

CHAPTER 5 SUMMARY TABLE

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Major Concept Description

Genetic gain of Increased function of the enzyme or transporter target due to multiple copies of the gene
function or gene polymorphism resulting in altered structure of the resulting target molecule

Genetic loss of Decreased function of the enzyme or transporter target due to failure of expression of the
function gene or altered structure of the resulting target molecule

Synonymous If an SNP results in no change in the amino acid specified by a given DNA base triad, it is
and referred to as a synonymous SNP and no change in phenotype is expected. If the SNP
nonsynonymous results in coding of a different amino acid, it is nonsynonymous and a change in function
SNPs may or may not result

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