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Pharmacogenetics
Dr. Rachel
F. Tyndale, Head
 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).
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