Genes and drug responses 5/9/02. By Richard Twyman Variations in genes can have dramatic impacts on the usefulness or effectiveness of a drug. And many different types of genes can be involved: drug receptors, the downstream targets, drug transporters and enzymes that metabolise drugs.

Polymorphisms in drug receptors: asthma and beta-2-agonists

Millions of people suffer from asthma, a disease characterised by the constriction of bronchial tubes and chronic breathing difficulties, often in response to poor air quality. Acute asthma attacks are normally treated by the inhalation of drugs such as albuterol, which relieve the symptoms of the disease by dilating the bronchial tubes.

Albuterol works by activating beta-2-adrenergic receptors on the surface of bronchial cells and thus causing the smooth muscles of the respiratory system to relax. However, not all asthma sufferers respond well to such beta-2-agonists, and this difference in response has been traced in some cases to a polymorphism in ADRB2, the gene encoding the beta-2-adrenergic receptor.

There are several single nucleotide polymorphisms in and around the ADRB2 gene, four of which occur in the coding region and affect the structure of the receptor. One of these, an allele that replaces the normal arginine residue at position 16 with glycine, is associated with the reduced response to albuterol. Patients homozygous for this allele (those with two copies) are five times less likely to respond to albuterol compared to those with the normal, arginine allele. The frequency of the glycine allele varies in different ethnic groups, from 40 per cent in Asian populations to 60 per cent in Caucasian populations.

Polymorphisms in several other genes have also been linked to variability in the response to asthma treatment.

Polymorphisms in drug receptors: High blood pressure and ACE inhibitors

Blood pressure can be raised through the action of a hormone called angiotensin. This hormone is produced constantly by the liver, but as an inactive precursor which must be converted to its active form by two enzymes.

The second enzyme in the pathway is called angiotensin converting enzyme (ACE) and drugs that block its activity (ACE inhibitors) are widely used to treat high blood pressure.

There is great variation in the response to ACE inhibitors and this may reflect polymorphisms in the ACE gene, which encodes the angiotensin converting enzyme. Unlike the beta-2-adrenergic receptor (see asthma), the major variant in the ACE gene known to be associated with the drug response is not a single nucleotide polymorphism but an insertion/deletion polymorphism reflecting the presence or absence of an Alu element (a piece of repetitive DNA).

In some populations, it is the presence of the insertion that confers a favourable drug response while in others it seems that the absence of the insertion is preferable. Further studies are therefore needed to determine the exact relationship between polymorphism in the ACE gene and the response to ACE inhibitors.

Polymorphisms in downstream targets: Alzheimer's disease and tacrine

The onset and progress of neurodegenerative diseases such as Alzheimer's and Parkinson's depends both on our genetic susceptibilities and the environment to which we are exposed. An important genetic determinant in Alzheimer's disease is the APOE gene, which encodes a protein called apolipoprotein E (Apo E). This protein may play multiple roles in the disease and its exact relationship to the drugs used to treat Alzheimer's is unknown.

The presence of two single nucleotide polymorphisms in this gene yields three common variants, APOEe2, e3 and e4, which produce proteins known as Apo E2, E3 and E4. Each of these variants is associated with a different level of susceptibility to the disease, APOE e4 conferring the greatest risk and APOE e2 the lowest risk.

Interestingly, Alzheimer's patients in the highest-risk group (those homozygous for the APOE e4 variant) also show the poorest response to tacrine, an acetylcholinesterase inhibitor, which acts by increasing the amount of acetylcholine in the brain. Acetylcholine is a neurotransmitter, a molecule that helps nerves communicate with each other. It is depleted in the brains of Alzheimer's patients and one way to slow the progress of the disease is to inhibit the enzyme acetylcholinesterase, which breaks acetylcholine down. While these high-risk patients reap little benefit from tacrine, they show the best response to S12024, a drug that increases blood pressure in the brain.

Polymorphism in drug transporters: MDR1

The MDR1 protein is a transporter that pumps molecules out of the cell. It can export many important drugs, including digoxin (which is used to treat heart problems), cyclosporin A (which is used to treat immune disorders and transplant rejection) and paclitaxel (which is used to treat cancer).

MDR1 is found in the intestine, where it affects drug absorption from the gut, and in the liver and kidneys, where it influences drug elimination. It is also found in the brain, and therefore controls drug penetration of the nervous system. Cancer cells often have higher MDR1 activity than normal cells, which gives them multi-drug resistance - hence the name MDR.

The response to these drugs varies widely and there are also many side effects. Some of this variability may be due to polymorphisms in the MDR1 gene. A number of polymorphisms have been identified but so far only one, a variant called C3435T, has been shown to have an obvious effect.

Clinical studies have shown that the C3435T polymorphism affects the way digoxin is removed from cells and this could be used in the future to determine the most suitable dose regimen for patients with heart failure. Interestingly, the same polymorphism appears to have no effect on the removal of cyclosporin A.

Polymorphisms in drug metabolisers: The cytochrome P450 system

Most of the drugs we use are broken down in our bodies by one group of enzymes, known as the cytochrome P450 (CYP) family. The genes encoding these enzymes are highly polymorphic and this variability plays an important role in the way we respond to a broad spectrum of drugs.

One well-characterised gene, CYP2D6, has over 70 variants, about 20 of which encode non-functional proteins. Individuals with two copies of such non-functional alleles are known as poor metabolisers, and are likely to show adverse reactions to about 100 common drugs, including nortriptyline (which is used to treat depression) and clozapine (an antipsychotic).

Poor metabolisers for these drugs account for about 10 per cent of Caucasian populations, 5 per cent of African populations but only 1-2 per cent of Asian populations. Similarly, individuals homozygous for non-functional alleles of the CYP2C19 gene are poor metabolisers of the sedative diazepam, and those with non-functional alleles of the CYP2C9 gene are unusually sensitive to ibuprofen.

CYP enzymes do not just eliminate drugs, they may also activate them. For example, opioid painkillers such as codeine are actually administered in an inactive form known as a prodrug. The active form of the drug is synthesised in the body by the activity of CYP enzymes. In the case of codeine, activation is mediated by CYP2D6. Poor metabolisers therefore get little analgesic benefit from codeine because the effective form of the drug is not made. The body also fails to make its normal quota of natural opioids, and such individuals may therefore have a lower pain tolerance than normal metabolisers.

At the other end of the scale are ultra-rapid metabolisers, who usually have multiple copies of particular CYP genes. For these individuals, normal doses are ineffective because the drugs are rapidly broken down.

It is therefore very important to establish the metabolic profile of individual patients, since this will prevent ineffective treatments (underdosing) and adverse drug reactions (overdosing) for a large number of drugs.