Pharmacogenetics: Research Annual Report 2003

Section Head: Dr. Rachel F. Tyndale

People have genetic differences in the amount and type of drug-metabolizing enzymes they produce. Genetic variation can cause people to metabolize drugs slowly or quickly, resulting in wide ranges in levels of drugs and drug metabolites (products of drug metabolism) among different people. Such variations can result in therapeutic failure and unanticipated toxicity.

Researchers in the Pharmacogenetics Section are inter-ested in genetic variations in enzymes and the effect these variations can have on the metabolism of drugs of abuse. Specifically, we are investigating how genetic variations in drug metabolism affect the pharmacology of specific drugs, the risk for specific drug dependencies and the amount of a drug used by people who are dependent on it (pharmaco-genetics). We investigate this using studies involving abuse liability, and epidemiological, genetic, biochemical and therapeutic intervention studies.

At the same time, we are examining how exposure to drugs of abuse may alter or regulate the levels of metabolizing enzymes. These studies use humans and animal models combined with behavioural, biochemical, immunological and molecular biological techniques. We hope that our studies will help us to develop novel approaches to identify and treat people who have a high risk for substance dependence.
Our data illustrate how genetic variation in drug metabolism, such as the inactivation of nicotine or alcohol, can åalter the risk for becoming dependent on nicotine or alcohol. We can now initiate studies where we manipulate the activity of an enzyme (e.g., with inducers or inhibitors) to imitate the protection from drug dependence found in the genetic studies.

This year, we also published a number of reviews on pharmacogenetics and drug dependence, as well as a review on the potential roles of CYP enzymes within the brain.

Variation in Nicotine Metabolism

Much of our recent work has focused on how genetic variation in the inactivation of nicotine affects aspects of smoking.

Nicotine is the psychoactive substance (drug) responsible for tobacco dependence; smokers adjust their cigarette consumption to maintain nicotine levels in the brain. In humans, 80 per cent of nicotine is metabolized to the inactive metabolite cotinine.

In our earlier work, we identified and characterized the liver enzyme responsible for this metabolism as the genetically variable CYP2A6. Genetic variation in this enzyme results in slower nicotine removal, prolonged higher brain levels of nicotine and, consequently, decreased smoking. People with defective CYP2A6 were protected from becoming tobacco-dependent and may be at lower risk for cancer due to both decreased smoke exposure and decreased activation of tobacco smoke procarcinogens.

We are studying the role of genetic variation in adults who have already become, or have not become, smokers. In addition, through collaborations in Montreal and California, we are investigating how variable metabolism of nicotine alters the development of nicotine dependence and smoking behaviour. In one study, we have been following adolescents as they learn to smoke; in another, we are studying college students and their smoking behaviours.

Recently, we have been identifying novel defective alleles in this gene. In 2002, we published the characterization of three new gene variants that also alter nicotine metabolism. Many more uncharacterized variants are likely to exist and remain to be investigated. We investigate these novel alleles in a number of ethnic populations as the frequency of a specific form of the enzyme can be very different among different groups.

We can mimic the effect of defective CYP2A6 by administering inhibitors of the enzyme. We have shown that use of an inhibitor can decrease the amount smoked and also decrease the amount of procarcinogen activation.

We have just completed a study of CYP2A6 in collaboration with a group in Kansas City, demonstrating that people who are slower nicotine metabolizers are able to quit smoking more effectively than those with more rapid metabolism. This increases our evidence that inhibiting the enzyme, thereby decreasing nicotine metabolism, may be useful for helping people quit smoking.

Variations in Alcohol Metabolism

In addition to the CYP2A6 gene, we continue to study the genetics of other CYP enzymes, including CYP2e1. CYP2e1 is able to metabolize alcohol and is thought to play a role in metabolizing different compounds in the brain.

We have found that people with a specific genetic form of this enzyme, when exposed to ethanol or other inducers, make much more of this enzyme. Our genetic studies have also shown that these people are more likely to become dependent on alcohol and also on nicotine. Again, like CYP2a6, the frequency of genetic variants for CYP2e1 varies substantially among ethnic groups.

Variations in MDMA Metabolism

This year, we also discovered that a number of "designer drugs" and clinically used drugs are potent inhibitors of specific drug-metabolizing enzymes. A commonly used recreational drug, MDMA (ecstasy), is metabolized very differently among people with different genetically variable enzymes.

Enzyme Variations in the Brain

In addition to our genetic studies, we have studied the presence and regulation of drug-metabolizing enzymes in the liver and brain. In the brain, we have used animal studies and human autopsy tissues to show that both nicotine and alcohol can profoundly alter the levels of these enzymes and that the effects of these drugs are very different in different parts of the body.

We have characterized the distribution in rat and human brain of three important enzymes, CYP2B6, CYP2E1 and CYP2D6. We found that the enzymes can be increased or decreased in rat brain by exposure to nicotine or alcohol and that the enzymes are higher or lower in brains from humans who were smokers or alcohol-dependent.

Besides alcohol and nicotine, these enzymes can activate or inactivate many drugs that act in the brain (e.g., antidepressants, neurotoxins); having more or less enzyme in the brain may alter the amount of active drug or neurotoxin in this organ. People who smoke or are alcohol-dependent may, therefore, have altered responses to drugs that act in the brain and may be more or less susceptible to neurotoxins. These enzymes may play a role in some of the psychiatric diseases where certain pathways in the brain are damaged (e.g., alcoholism, Parkinson's disease, Alzheimer's disease).

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