Chapter 18

Pharmacogenetics and
Pharmacogenomics
INTRODUCTION
 One area of personalized genetic medicine is drug therapy
based on pharmacogenetics.
 Pharmacogenetics is the study of differences in drug
response due to allelic variation in genes affecting drug
metabolism, efficacy, and toxicity.
In one year in USA:
> 1 billion prescriptions
10s billions of drug doses
> 10,000 different medications
> 2,000,000 patients with adverse drug
>100,000 excess deaths.
So, the development of pharmacogenetics is likely to have
immediate benefit
 Pharmacogenetics is relevant to individual
variation in drug response in two ways
 The first is variation in pharmacokinetics, that is,
the rate at which the body absorbs, transports,
metabolizes, or excretes drugs or their metabolites.
 The second is the variation affecting the
pharmacodynamics of a drug, that is, the genetic
causes of variability in the response to the drug due
to allelic variation in the drug's downstream targets,
such as receptors, enzymes, or metabolic
pathways.
"If it were not for the great variability among individuals
medicine might as well be a science and not an art." The
thoughts of Sir William Osler in 1892 reflect the view of
medicine over the past 100 years. The role of physicians in
making the necessary judgements about the medicines that
they prescribe is often referred to as an art, reflecting the lack
of objective data available to make decisions that are tailored
to individual patients. Just over a hundred years later we are
on the verge of being able to identify inherited differences
between individuals which can predict each patient's response
to a medicine. This ability will have far-reaching benefits in the
discovery, development and delivery of medicines. Sir William
Osler, if he were alive today, would be re-considering his view
of medicine as an art not a science.
 Using Risk Information to Improve Care: Pharmacogenetics
 Variation in Pharmacokinetic Response
 Variation in Phase I Drug Metabolism: Cytochrome P450

Typical hydroxylation reactions carried out by cytochrome P450

enzymes in phase I metabolism.
Typical phase II conjugation reactions to inactivate drugs and
create soluble drug metabolites for excretion
 Human cyto P450 proteins are a large family: 56 enzymes.
 P450 enzymes are heme-containing proteins in the liver.
 Fe+2 in heme allows them to accept electrons from electron
donors, such as NADPH, and use them for catalyzing a
number of different reactions, the most common of which is
addition of an oxygen atom from O2 to a carbon, nitrogen, or
sulfur atom.
 For many drugs, the action of cyto P450 is to add a –OH to
the molecule, a typical step in what is referred to as phase I
of drug metabolism, defined as the introduction of a more
polar group to a compound that allows a side group to be
more readily attached.
 The hydroxyl group attached in phase I provides a site for a
sugar or acetyl group to be attached to the drug to detoxify it
and make it much easier to excrete in what is referred to
as phase II of drug metabolism.
 The cytochromes P450 are grouped into 20 families according
to amino acid sequence homology.
 Three of these families-CYP1, CYP2, and CYP3-contain
enzymes that are promiscuous in the substrates they will act on
and that participate in metabolizing a wide array of substances
from outside the body (xenobiotics), including drugs.
 Six genes in particular (CYP1A1, CYP1A2, CYP2C9,
CYP2C19, CYP2D6, and CYP3A4) are especially important for
pharmacogenetics because the six enzymes they encode are
responsible for phase I metabolism of more than 90% of all
commonly used drugs. CYP3A4 alone is involved in the
metabolism of over 40% of all drugs used in clinical medicine.
 Furthermore, many of the CYP genes are highly polymorphic,
with alleles that have real functional consequences for how
individuals respond to drug therapy.
Contribution of individual cytochrome P450 enzymes to
phase I drug metabolism.
Table 18-1. Polymorphic Cytochrome P450 Genes Involved in Drug Metabolism
Family Gene Alleles of Functional Significance* Drugs Metabolized (Selected)
CYP1 CYP1A2 ↑ and ↓ activity alleles Caffeine, Propranolol
CYP2 CYP2C9 ↑, ↓, and 0 activity alleles Angiotensin II receptor blockers
Nonsteroidal anti-inflammatory drugs
Metronidazole, Oral hypoglycemics
Warfarin
CYP2C19 ↓ and 0 activity alleles Antiepileptics, Antidepressants
Antianxiety drugs
CYP2D6 ↑, ↓, and 0 activity alleles Antiarrhythmics
Antidepressants
Antipsychotics
Beta-adrenergic blockers
Narcotic analgesics
CYP3 CYP3A4 ↑, ↓, and 0 activity alleles Acetaminophen
Antifungals
Cocaine
Codeine
Cyclosporine A
Diazepam
Erythromycin
Cholesterol-lowering statins
Taxol, Warfarin
*↑, one or more alleles with increased activity; ↓, one or more alleles with reduced activity; 0, one or
more alleles with no activity.
CYP alleles can result in absent, decreased, or increased
enzyme activity, thereby affecting the rate at which many drugs
are metabolized. CYP2D6, for example, is the primary cytochrome
in phase I metabolism of more than 70 different drugs. There are
26 alleles in the CYP2D6 gene that affect activity and are
classified as reduced, absent, or increased activity alleles

Metabolizer Phenotypes Arising from Various Combinations of

CYP2D6 Allele on One Chromosome

wild-type reduced absent increased

Allele on Other wild-type normal
Chromosome reduced normal poor
absent normal poor poor
increased ultrafast - - -
 Three main phenotypes are generally recognized: normal
metabolizers, poor metabolizers, and ultrafast metabolizers

A, Poor metabolizer accumulates drug to toxic levels. B, Normal

metabolizer reaches steady-state levels within the therapeutic
range. C, Ultrafast metabolizer fails to maintain serum levels
within the therapeutic range.
Frequency of Poor CYP2D6 and CYP2C19 Metabolizers in
Various Population Groups

Population Frequency of Poor

Ethnic Origin of Population Metabolizers (%)
CYP2D6 CYP2C19
Sub-Saharan Africa 3.4 4.0
Amerindian 0 2.0
Asian 0.5 15.7
White 7.2 2.9
Middle Eastern/North Africa 1.5 2.0
Pacific Islander 0 13.6
 Variation in Phase II Metabolism
 Glucuronidation Polymorphism and Camptothecin
Toxicity
 One important phase II metabolic pathway is
glucuronidation by UDP-glycosyl-transferase, which is part
of the normal metabolic pathway for bilirubin excretion into
bile. UGT1A1 encodes a glucuronate transferase.
 The UGT1A1*28 allele is frequent in most ethnic groups
worldwide. Case-control studies of patients receiving
camptothecin have shown a 3-fold to 5-fold higher relative
risk for serious toxicity from typical chemotherapy regimens
in individuals homozygous forUGT1A1*28. Heterozygotes
may also be at increased risk.
Frequency of UGT1A1*28 Genotypes in Various Population
Groups

UGT1A1*28 Genotypes Frequency (%)

Region/Country
*1/*1 *1/*28 *28/*28
Sub-Saharan Africa 30 36 34
Southeast Asia 80 19 1
China 78 20 2
Europe 44 47 9
Indian subcontinent 29 49 22
Pacific (Papua New Guinea) 97 3 0
South American Amerindian 33 18 7
  Second important phase II pathway in drug metabolism is
acetylation: N-Acetyltransferase Polymorphism and
Tuberculosis Therapy with Isoniazid
 Polymorphism in Thiopurine Methyltransferase and 6-
Mercaptopurine Efficacy
 Cholinesterase Polymorphism and Prolonged
Postoperative Paralysis
Frequency of Slow-Acetylator Phenotype
Population Frequency (%)
Sub-Saharan Africa and 51
African American
White 58
Chinese 22
Japanese 10
Inuit 6
 Variation in Pharmacodynamic Response
 Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
and Hemolytic Anemia
 Malignant Hyperthermia is most frequently associated
with mutations in a gene called RYR1, encoding an
intracellular calcium ion channel.
PHARMACOGENOMICS

 Pharmacogenomics, the genomic approach to

pharmacogenetics, is concerned with the assessment of
common genetic variants in the aggregate for their
impact on the outcome of drug therapy.
 We expect genomic approaches to pharmacogenetics to
become increasingly more important in the delivery of
personalized genetic medicine in the years ahead.