164165CHAPTER 6

The Application of Genomics to Pharmacology

Emma L. Kurnat-Thoma

Differences in how individuals respond to drugs can be due to genetic or nongenetic factors. Certain individuals may require different doses of the same drug in order to achieve maximum effectiveness, others may not respond at all to certain drugs, and different adverse reactions may be manifested. Much of this variability is thought to be genetic, and some families may be at greater risk for adverse events than the population at large. The well-known and recently discovered polymorphisms in the genes coding for enzymes affecting drug metabolism, transport, disposition, excretion, and drug receptors affect large numbers of persons worldwide. Their clinical significance depends on a variety of factors, which are not directly genetic (e.g., age, weight, general health, liver function) as well as the therapeutic index of the drug. However, a person’s genetic predisposition can influence any stage of the drug-handling process, as listed in Box 6.1.

Pharmacogenetics is the study of variable drug response and drug adverse events as a result of a person’s heritable genetic differences. Pharmacogenomics is a more recent term, and is the study of how drugs impact the total genome and interact with its expression output. This includes how drugs act on and with gene variations, protein expression, and other biology network applications such as the human microbiome (the microbial genomes of bacteria, bacteriophage, fungi, protozoa, and viruses that live inside and on the human body). Pharmacogenetics and pharmacogenomics are often used interchangeably to denote drug therapies tailored to an individual’s DNA, but they really mean distinctly different things. Figure 6.1 provides an overview of pharmacogenomics in today’s health care setting.

FIGURE 6.1. Clinical Premise of Pharmacogenetics and Pharmacogenomics.

Source: National Human Genome Research Institute (2014).

167Genetic variation in drug metabolism and handling can be quantitative or qualitative. For example, mutant genes may produce enzyme variants with high, intermediate, low, or absent activity. The degree and type of variation in an individual’s response may not be apparent if there is no important, easily detected consequence. Someone who has even a low level of activity for a given enzyme may have enough functioning product to cope normally unless some unusual stressor such as infection or trauma is encountered. Therefore, this person may be unaware of the impairment.

Information about response variation is particularly important in drugs with a narrow therapeutic margin, or therapeutic index. This means there is little difference between toxic and therapeutic doses; a classic example is the widely prescribed anticoagulant warfarin (Coumadin). Thankfully, many drugs have a wide enough margin of safety so that even with individual-response variation, effectiveness and safety are not dangerously compromised. However, practitioners must recognize that just as there can be variable responses in patients due to their age differences, persons from diverse racial and ethnic groups may respond differently to medications because of their genetic differences. Drug developers are increasingly using genetic and genomic knowledge to tailor disease treatment approaches.

Inherited drug receptor mutations can also cause functional changes with health implications, such as an individual’s opiate receptor variability and their risk for drug dependence. Other drug receptor variants can result in resistance to vasopressin, estrogen, insulin, and the steroid hormones. Current research studies differences in the metabolism of alcohol and illicit drugs to generate new information about the genetics and biology of drug dependence and addiction.

Variations can be relatively common in certain populations—such as the case with polymorphisms, or they may be relatively rare. Some pharmacologically significant variations include:

In this chapter, both pharmacogenetic disorders and common polymorphisms leading to altered response to drugs are discussed, as are pharmacogenomic applications and the ethical problems engendered.

COMMON GENE MUTATIONS AND VARIATIONS AFFECTING DRUG METABOLISM

There are a number of genetic mutations and common polymorphisms that affect the way drugs are metabolized. A relatively common human enzyme genetic condition, glucose-6-phosphate dehydrogenase (G6PD) deficiency, is discussed in the following text. Also included in this chapter are polymorphisms in the drug-metabolizing enzymes such as cytochrome P-450 superfamily; acetylator variation; and 168thiopurine-S-methyltransferase polymorphisms. Common variations that affect drug metabolism and handling in clinical practice are shown in Table 6.1.

169Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a genetic condition and is the most common enzyme abnormality known. G6PD deficiency was thought to have a protective effect against malaria, leading to its maintenance in the human population. It affects approximately 400 million people throughout the world, especially those of Mediterranean, African, Middle Eastern, Near Eastern, and Southeast Asian origin. Most persons with G6PD deficiency are not diagnosed due to mild or confounding clinical manifestations.

G6PD deficiency results from functional mutations or polymorphisms in the 18-kb G6PD gene located on the long arm of the X chromosome (Xq28); thus, males are hemizygous. Although there are more than 400 identified G6PD variants, not all are clinically significant. There are presently 187 known mutations in the G6PD gene that result in the disease phenotype, with 35 mutant polymorphic alleles. Disease severity is determined by the percentage of active G6PD enzyme present from the patient’s specific G6PD mutation or variant. Various classifications exist and include:

Approximately 10% to 15% of Black males in the United States have G6PD deficiency. In some areas of the Middle East, G6PD deficiency may be as high as 35% of males. Because of this high frequency, more homozygous females are found to be G6PD deficient than any other X-linked recessive disorder. Unlike males, whose red blood cells are all affected by a G6PD mutation, females who are heterozygous (one mutant allele, one normal allele) have two types of red blood cells: those that are normal and those that are G6PD deficient. Although the two types of red blood cell populations are usually about 50:50, X inactivation (see Chapter 4) can lead to unequal distribution. For example, females with more G6PD deficient cells (i.e., 30% normal, 70% deficient) are more susceptible to manifesting symptoms of the disease.

G6PD plays a key role in carbohydrate metabolism by producing ribose 5-phosphate and generating NADPH (see Glossary) in the hexose monophosphate pathway (also called pentose phosphate pathway). G6PD is found in all cells where it is needed to catalyze these reactions and maintain an adequate level of intracellular NADPH. For most cells, other metabolic pathways such as the citric acid cycle can provide the needed end products from this reaction.

In red blood cells, G6PD provides reductive capacity by producing NADPH—and is the only pathway available. While G6PD-deficient red blood cells can usually function well, their cell membrane integrity can become compromised in the presence of an oxidative challenge or stress, leading to accelerated destruction (hemolysis). Triggering stress events include:

Presenting signs and symptoms can include jaundice, fatigue, pallor, tachycardia, splenomegaly, and shortness of breath; the major clinical consequences requiring supportive treatment are:

Hemolysis typically begins within 24 to 72 hours of starting the oxidative drug, ingestion of fava beans (a common dietary component in the Mediterranean, Middle and Far East, and North Africa), or onset of acute infection (usually severe, such as typhoid fever, rickettsial infections, or viral hepatitis). Seasonal favism may be encountered after harvests, when fava beans are more plentiful. Classic clinical trajectories include (a) development of Heinz bodies in the red cells, (b) red blood cell destruction with resulting drop in hemoglobin, and (c) hemolytic anemia with dark urine, back and abdominal pain, and jaundice. Acute renal failure can often occur in G6PD-deficient persons with hepatitis or urinary tract infections. Chronic nonspherocytic hemolytic anemia accompanies certain G6PD variants and may be exacerbated by stress, infection, or drug intake. There may be a history of neonatal jaundice, as well as gallstones, splenomegaly, decreased stamina, weakness, iron overload, or progressive hepatic damage. Recovery from acute hemolytic anemia in G6PD deficiency requires removal of the offending stressor or agent. Clinical improvement usually takes place on its own but, if a clinical course is severe, red blood cell transfusion(s) and close observation or support of the patient’s cardiorespiratory status are needed.

In people with G6PD-deficiency, hemolysis following the intake of the antimalarial drug primaquine was described in 1953. Since the original work, WHO has identified three classifications of drugs: (a) those that everyone with G6PD-deficiency should avoid; (b) those that G6PD-deficient persons of Mediterranean, Middle Eastern, and Asian origin should avoid; and (c) those that persons with the African (A-) variant should avoid. In some cases, use of a particular drug depends on the importance and dosage required. Other factors that influence response to these drugs include patient age, severity of the G6PD deficiency, hemoglobin level, factors relating to the red blood cell, presence of additional oxidative stresses such as infection, and other additional genetic differences.

Drugs and chemicals that cause adverse effects in persons with G6PD deficiency vary according to author. Selected major drugs to avoid are acetanilide, dimercaprol, dapsone, flutamide, methylene blue, nalidixic acid, naphthalene, niridazole, nitrites, 171and nitrofurans including furazolidone, nitrofurantoin, nitrofurazone-pamaquine, pentaquine, phenazopyridine, phenylhydrazine, primaquine, sulfacetamide, sulfamethoxazole, sulfanilamide, sulfapyridine, toluidine blue, sulfone antimalarials, triazole, and trinitrotoluene. In addition to quinine water, mothballs and fava beans should be avoided.

Some researchers recommend screening all individuals in certain at-risk population groups before prescribing any of the previously listed drugs. Awareness of this deficiency has become important when prescribing drugs to treat HIV infection, such as the case for dapsone. In some instances, the need for the drug outweighs the risk of hemolytic anemia. Nursing implications are provided in Box 6.2.

Cytochrome P450 Polymorphisms (CYPs)

The hepatic cytochrome P450 (CYP) enzyme system comprises a group of related enzymes known as a superfamily (sharing common amino acid sequences within and across human, animal species). The P450 enzymes are responsible for oxidizing many chemicals and drugs. A separate gene codes for each, and more than 200 have been identified, some of which have multiple allelic forms. P450 enzymes are categorized into family and subfamily groups based on the percentage of sequence homology at the amino acid level, and are named according to the following system: CYP followed by a family number, a subfamily letter, and a number for the individual form (e.g., CYP4A11). Box 6.3 outlines some of the major human cytochrome P450 forms in humans.

While each CYP subfamily group has different numbers of genetic variants, clinically they fall into several functional categories: (a) ultrarapid, extensive activity (considered normal), (b) intermediate activity, and (c) low functional activity. Frequencies of these categories often vary in populations by ethnic ancestry. In general, poor metabolizers break down drugs more slowly, causing circulating blood levels of the drug to stay higher for longer periods of time, increasing the risk of toxicity. Poor metabolizers also need less frequent dosing to obtain optimum therapeutic effect without adverse reactions. Persons who are ultrarapid metabolizers, on the other hand, may need more frequent dosing, may not show expected therapeutic effectiveness, and may be classified as treatment failures. For some variants, genotyping is now available clinically in order to maximize drug effectiveness and prevent serious adverse reactions. Clinically important cytochrome P450 genetic variations are summarized in Table 6.2. Of particular interest to nurses is the inhibited metabolism of codeine in poor metabolizers of CYP2D6 who receive no analgesic effect from codeine. When a patient is not getting the expected pain relief from codeine, the reason may be genetic, and the nurse must help them find appropriate analgesic relief, not increase the dose of codeine or decide the patient is “faking.”

Acetylator Status and Drug Metabolism

The N-acetyltransferase (NAT) enzymes transfer acetyl groups to a substrate by using acetyl coenzyme A (CoA), and are responsible for varied functions such as regulation of circadian rhythm (melatonin, serotonin synthesis in response to light/dark cycles), mood and behavior, and chromatin remodeling (histone acetyltransferase). While approximately 18 genes are thought to encode NATs, the ability to metabolize and eliminate certain drugs depends on acetylation in the liver by NAT1 and NAT2. Both are known to have important roles in the detoxification of carcinogens and interaction with toxic environmental hazards, such as cigarette smoke. NAT1 is expressed ubiquitously and NAT2 is found primarily in the liver. Each has multiple alleles (28 for NAT1, 88 for NAT2), which are designated by an asterisk and allele number, for example, NAT2*5B.

174While the importance of acetylator status was first recognized during therapy for tuberculosis with isoniazid (INH), drug efficacy and toxicity are currently linked to NAT1 and NAT2 function for a number of drugs. This includes the anti-infective drugs isoniazid (tuberculosis), dapsone, and sulfamethoxazole (Pneumocystis fungi); the cardiovascular medications hydralazine (antihypertensive) and procainamide (antiarrhythmic); caffeine; the anti-inflammatory, immunomodulating agent sulfasalazine (used to treat ulcerative colitis, Crohn disease, and arthritis); the monoamine oxidase inhibitor phenelzine (antidepressant); and the benzodiazepine nitrazepam (antianxiety, sedative).

Individuals can be categorized into the following three basic phenotype groups: slow or poor, rapid, and ultrarapid acetylators. Slow acetylators maintain higher serum levels of these drugs than do rapid acetylators. In general, slow acetylator individuals are more likely to experience greater therapeutic response, but are also at risk for higher incidence of side effects than rapid acetylators. NAT2 slow acetylators may be at greater risk for the development of spontaneous systemic lupus erythematosus (SLE) after receiving the drugs hydralazine and procainamide. In North American and European populations, between 50% and 70% are slow acetylators, as are about 90% of some Mediterranean populations such as Egyptians and Moroccans. In eastern Pacific populations such as Chinese, Korean, Japanese, and Thai, about 10% to 30% are slow acetylators, as are about 4% of Alaskan Natives. There are also a number of studies that identify association of NAT1 and NAT2 genotype with risk of cancer development and cancer treatment resistance, but need confirmation to be conclusively established. Fast acetylators who eat meat may have a higher risk for colorectal cancer and slow acetylators may have a higher risk for bladder cancer when exposed to arylamines and cigarette smoke.

Thiopurine S-Methyltransferase (TPMT)

 

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