Pharmacogenetics: CAMH Research Annual Report 2002

Genetic variations in people's ability to metabolize drugs can result in therapeutic failure and unanticipated toxicity due to too much or too little metabolism of a drug. In addition to clinically used drugs, researchers of the Pharmacogenetics Section, led by Drs. Rachel F. Tyndale and Edward M. Sellers, explore the role that genetic variation in drug-metabolizing enzymes can have on metabolism of drugs of abuse. The section investigates how such genetic variation can alter the risk for specific drug dependencies and alter the amount of a drug used by dependent individuals, and focuses on identifying high-risk individuals and developing novel treatment approaches. A second line of research investigates the expression and regulation of drug-metabolizing enzymes in the brain. These enzymes can alter drug levels in the immediate vicinity of drug targets such as receptors and transporters. They are also responsible for creating toxic byproducts that may lead to neurotoxicity. CYP enzymes in the brain are both genetically variable (they exist in some people and not in others) and environmentally regulated (the levels and distributions in the brain can be altered by drugs of abuse).

Research from the section has demonstrated a number of actions that metabolic variations can have on pharmacology and dependence risk profile of specific drugs. For example, genetic variation in an enzyme could alter activation of a drug to a more potent drug metabolite of similar pharmacology (e.g., codeine activation to morphine by CYP2D6). It can also create differences in metabolic patterns via variant alleles (e.g., methamphetamine is metabolized to different toxic metabolites by some people). Genetic variations can alter metabolism of drugs in which the parent drug and metabolite have similar effects but different durations of action (e.g., flunitrazepam and CYP2C19) and it can alter the activation of a drug to a metabolite that has different pharmacology (e.g., dextromethorphan to dextrorphan via CYP2D6). Variable drug metabolism can also convert an active parent drug to an inactive metabolite (e.g., nicotine to cotinine by CYP2A6).

The Pharmacogenetics Section investigates these variations using abuse liability, epidemiological, genetic, biochemical and therapeutic intervention studies. The Pharmacogenetics Section accomplished the following research goals during 2001.

New Publication in Pharmacogenomics

Dr. Tyndale, with Werner Kalow and Urs A. Meyer, co-edited the book, Pharmacogenomics (Drugs and the Pharmaceutical Sciences series, Marcel Dekker Inc., New York, 2001), outlining current pharmacogenomic techniques and applications. This book includes techniques used by both academic and industrial laboratories, for both small-scale and high-throughput requirements.

Enzyme Variations, Medications and Drug Metabolism

In collaboration with Dr. Deborah Mash of Miami (Professor, University of Miami School of Medicine), we showed that ibogaine, a drug being tested for addiction treatment, is metabolized by the genetically polymorphic enzyme CYP2d6. Treatment dose and outcomes are altered by this genetic variation -- rapid metabolizers need larger doses and get better therapeutic outcomes.

The section has also collaborated with Dr. Allan Okey (Professor, Department of Pharmacology, University of Toronto) to investigate genetic variation in the aryl hydrocarbon receptor. This receptor, which is altered by smoking, regulates an enzyme involved in metabolizing antipsychotic drugs. In collaboration with researchers in Seattle, we determined the contribution of two genetically variable enzymes (CYP2C19 and cyp3a4) to the metabolism of flunitrazepam (Rohypnol®), a drug of abuse.

We also characterized other genetic variants of hepatic enzymes, including differences in drug metabolism for two genetic variants of CYP2d6. CYP2d6 is responsible for the metabolism of codeine and amphetamine as well as a number of clinically used drugs. We have also worked collaboratively to establish the frequencies of these genetic variants among different ethnic populations (e.g., CYP2C9).

Smoking Research

In the area of smoking research, we identified and characterized inhibitors of CYP2A6, the genetically variable enzyme that inactivates nicotine and alters smoking behaviour. These inhibitors can be used to decrease nicotine metabolism in vivo and to decrease smoking. We also identified the genetic variant CYP2A6*2 as being fully deficient for nicotine metabolism.

In addition, we used animal models to show that ethanol can increase the enzyme that metabolizes nicotine (CYP2B1) in the liver, and that nicotine can increase one of the enzymes that metabolizes ethanol (CYP2E1) in the liver. This work merges well with the group's ongoing investigations of the effects of ethanol on one of ethanol's target receptors, the gabaa receptor. Using a number of paradigms, we showed that ethanol can alter ethanol metabolism and gabaa receptor regulation (in collaboration with Richard W. Olsen, ucla, and Jose Nobrega and Denise Tomkins, CAMH).