Pharmacogenetics
Head: Dr. Rachel F. Tyndal
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. R. Tyndale and E.M. Sellers,
are interested in the role that genetic variation in drug-metabolizing
enzymes can have on metabolism of drugs of abuse. Specifically, the section
is investigating 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.
Research from the section has demonstrated a number of actions that variations
in metabolism 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 alter 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. One example of how genetic variation in the inactivation of a
drug (nicotine) alters drug-taking behaviour is illustrated below.
Nicotine is the drug responsible for tobacco dependence; smokers adjust
their cigarette consumption to maintain nicotine levels in the brain.
In humans, 60 to 80 per cent of nicotine is metabolized to the inactive
metabolite cotinine. Initially, we identified and characterized the liver
enzyme responsible for this metabolism as the genetically variable CYP2A6.
CYP2A6 can also activate tobacco smoke procarcinogens (e.g., NNK).
In early studies (Nature 393: 750, 1998), we demonstrated that
people with defective CYP2A6 alleles had significant protection from becoming
tobacco-dependent. We also provided evidence that, if tobacco dependent,
those people with defective alleles, resulting in decreased nicotine removal,
smoked fewer cigarettes. Therefore, people who have CYP2A6 defective alleles
may have a decreased risk of becoming smokers; smoke less if dependent;
and may be at lower risk for cancer due to both decreased smoke exposure
and decreased activation of tobacco smoke procarcinogens.
Subsequently, we have identified novel defective alleles, as well as
a CYP2A6 gene duplication, in smokers who have altered nicotine metabolism,
demonstrating altered carbon monoxide levels (indicating smoke exhalation),
plasma and urine nicotine and cotinine levels and cigarette counts. Together
these data illustrate how genetic variation in drug metabolism, in this
case the inactivation of nicotine, can alter the risk for becoming a smoker,
how much one smokes and how easy it is to quit smoking. These data have
provided the impetus to look at how manipulations of the CYP2A6 activity
might be useful in a therapeutic context.
We are currently extending this work by identifying multiple new CYP2A6
genetic variants and characterizing their effect on nicotine metabolism
and smoking. This is being done in multiple ethnic groups in addition
to the original data, which was generated in Caucasians. These data will
enable us to examine the role of this gene in smoking phenotypes from
multiple ethnic groups.
Further studies continue to investigate whether one could replicate the
genetic findings using inhibition of CYP2A6 to imitate the defective nicotine
metabolism and decreased smoking behaviour observed and to determine if
inhibition of the CYP2A6 could be useful therapeutically. Our data support
a role for CYP2A6 inhibitors in decreasing smoking in humans and decreasing
procarcinogen activation as part of an exposure reduction paradigm. In
other words, if one blocks the removal of nicotine in smokers, they have
a significantly reduced need to smoke, resulting in decreased smoking
behaviour and exposure and activation of tobacco smoke carcinogens. Inhibitors
of the CYP2A6 enzyme can block nicotine metabolism in people, providing
a new approach to treatment of tobacco dependence by making an oral nicotine
replacement therapy feasible (i.e., a nicotine pill versus a nicotine
patch or gum). In addition, we have initiated studies showing that CYP2A6
inhibitors can be used to improve the nicotine patch and gum, by increasing
the amount of nicotine that gets into an individual and keeping it there.
This leads to a better protection from withdrawal.
CYP2A6 inhibition alone, or combined with oral nicotine, decreases smoking
and the harm associated with smoking and therefore should have a role
in tobacco smoking cessation, exposure reduction or relapse prevention
strategies.
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