International Research Compendium - Drug Free Australia

substance use or dependence will become dependent, and likewise some of those
who become dependent will not carry that particular risk factor.
These genetic contributions to vulnerability seem likely to be distributed over several
distinct regions ( loci ) on the chromosomes. The chromosomes are made up of a
distinct set of instructions, (or genes) that “code” for proteins.
One overwhelming finding from genetic studies of psychoactive substances is that
the heritability ( genetic contribution ) of dependence for one substance correlates
highly with dependence for other substances. For example, recent studies of ethanol
and tobacco use by humans suggest that common genes may influence the
dependence on tobacco and ethanol.
People who smoke are also at greater risk for severe alcohol dependence. This may
occur by diminishing the effects of alcohol, because nicotine can increase the activity
of the alcohol-metabolising enzyme CYP2E1. Alcohol dependence is associated with
more serious nicotine withdrawal. Data from twin studies suggest that cigarette
smoking may contribute to the development of tolerance to the effects of alcohol and
a diminished sense of intoxication, suggesting that smoking induces increased
alcohol metabolism.
Twin studies that have been done in several countries over several decades show
evidence that addiction has an inheritable component. Regardless of the foster
parent family environment, adopted children developed alcohol abuse or abstinence
patterns similar to their biologic parent’s use of alcohol. Statistics (USA ) show that if
one biological parent were alcoholic, a male child was about 34% more likely to be an
alcoholic than the male child of non-alcoholics. If both biological parents were
alcoholic, the child was about 400% more likely to be alcoholic.
There are 2 main types of genes that have been associated with drug dependence:
those that are likely to be specific to the particular drug dependence and those that
may play a common role in either all or a subset of dependencies.
Genes related to smoking:
There is some evidence that smoking behaviour is associated with at least 14
different chromosomal locations. Studies suggest that the effect of any one gene on
smoking behaviour is likely to be weak. The genes involved in nicotine metabolism
may be important risk factors for smoking; for example, the metabolic enzyme
CYP2A6 is responsible for about 90% of the metabolic inactivation of nicotine to
cotinine.
Candidate genes for alcohol dependence:
Alcohol is metabolised to acetaldehyde, which in turn is metabolised to acetate
before elimination from the body. The mitochondrial form of aldehyde dehydrogenase
( ALDH2 ) is the enzyme primarily responsible for the metabolism of acetaldehyde to
acetate. ALDH2 deficiency leads to an averse response to alcohol due to elevated
levels of acetaldehyde, resulting in increased hangover symptoms, and the alcohol
flushing response.
Alcoholdehydrogenase ( ADH ) metabolises alcohol to acetaldehyde.
The subtype ADH2*2 is lower in populations with alcohol dependence, indicating a
protective effect.
Cytochrome P-450 2E1 ( CYP2E1 ) is a hepatic enzyme that also metabolises
ethanol to acetaldehyde. The levels of hepatic CYP2E1 activity in humans were
found to vary by 15-fold. Nicotine increases hepatic CYP2E1 activity.
Chronic ethanol consumption results in the induction of CYP2E1, which is believed to
play an important role in the pathogenesis of alcohol-induced liver disease and is
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