Nicotine Addiction: Is It Due To Genes?

All cigarettes can damage the human body. Any amount of smoke is dangerous.
Cigarettes are perhaps the only legal product whose advertised and intended
use--smoking-- is harmful to the body and causes cancer.

The nicotine in cigarette smoke causes an addiction to smoking. Nicotine is an addictive drug--just like heroin and cocaine--for 3 main reasons.

· When taken in small amounts, nicotine creates pleasant feelings that
make the smoker want to smoke more.

·  Smokers usually become dependent on nicotine and suffer withdrawal
symptoms when they stop smoking. These symptoms include nervousness, headaches,
irritability, and difficulty in sleeping.

· Because nicotine affects the chemistry of the brain and central nervous
system, it can affect the mood and nature of the smoker.

Although some people try to make their smoking habit safer by smoking fewer cigarettes, most smokers find that hard to do. Some people think that switching from high tar and nicotine cigarettes to those with low tar and nicotine content makes smoking safer, but this is not always true. When people switch to lower tar and nicotine brands, they often smoke more cigarettes or more of each cigarette to get the same nicotine dose as before.

Nicotine is a poison and in large doses can kill a person by stopping their
breathing muscles. Smokers usually take in small amounts that the body can quickly
break down and get rid of. The first dose of nicotine causes a person to feel
awake and alert, while later doses result in a calm, relaxed feeling. Nicotine
can make new smokers, and regular smokers who get too much of it, feel dizzy
or sick to their stomachs.

The resting heart rate for young smokers increases 2 to 3 beats per minute.
It also lowers skin temperature and reduces blood flow in the legs and feet.
Nicotine plays an important role in increasing smokers' risk of heart disease
and stroke.

Most people begin smoking as teens. Peer pressure and curiosity are the major reasons young people try smoking. Also, people with friends and parents who smoke are more likely to begin smoking than those who have nonsmoking parents. Those who begin to smoke at a younger age are more likely than late starters to develop long-term nicotine addiction.

Another prevalent influence in our society is the tobacco industry's ads for its products. The tobacco industry spends billions of dollars each year to create and market ads that show smoking as an exciting, glamorous, healthy adult activity.

Addiction to Nicotine

Anyone who starts smoking is at risk of becoming addicted to nicotine. Studies show that cigarette smoking is most likely to become a habit during the teen years. When young people become cigarette smokers they are more likely to become addicted. They are also more likely to suffer from the health problems caused by cigarette smoking.

Among US adults, cigarette smoking has declined from about 42% of the population in 1965 to about 23% in 2001 (the latest year for which numbers are available).About 46.2 million adults smoked cigarettes in 2001. About 25% of men and 21% of women were smokers. Education seems to affect smoking rates, as shown by a steady decrease in the smoking rates in groups with a higher level of education.

Tobacco use, including smoking cigarettes, chewing tobacco, and dipping snuff, remains common among American youth. Every day, more than 35% of adult smokers had become daily smokers by age 18. If current patterns of smoking persist, an estimated 6.4.million children in the US will not live full lives because of tobacco.

Tobacco use, including smoking cigarettes, chewing tobacco, and dipping snuff, remains common among American youth, according to the most recent National Youth Tobacco Survey.

Despite declines in recent years, more than 1 in 4 high school students (28%) used some type of tobacco in 2002, and more than 1 in 5 (23%) were considered current cigarette smokers. Cigar smoking was also common among high school students (about 12%).

About 13% of middle school students used some form of tobacco, with cigarettes (10%) being the most common. Tobacco use is higher among male students than among female students for all products except cigarettes, where the numbers are now about the same. Students who smoke are more likely to use other drugs, get in fights, carry weapons, attempt suicide, and engage in high-risk sexual behaviors.

Despite recent declines, about two-thirds (64%) of high school students have ever tried cigarette smoking and 15% of middle school students currently use some form of tobacco. Cigar smoking is also common among high school students. In 2001, about 15% of high school students were smoking cigars. Use was higher among male than among female students. Students who smoke are more likely to use other drugs, get in fights, carry weapons, attempt suicide, and engage in high-risk sexual behaviors.

A low-tar cigarette can be just as harmful as a high-tar cigarette when a person takes deeper puffs, puffs more frequently, or smokes cigarettes to a shorter butt length. Even if smokers who switch to lower tar brands do not make these changes to compensate, the health benefits are very small when compared to the benefits of quitting for good.

Cigarette smoke is a complex mixture of organic and inorganic compounds produced by the burning of tobacco and additives. The smoke contains tar, which is made up of over 4,000 chemicals, including over 60 known to cause cancer. Some of these substances cause heart and lung diseases, and all of them can be deadly. You might be surprised to know some of the chemicals found in cigarette smoke.

They include:

• cyanide
  
• benzene
  
• formaldehyde
  
• methanol (wood alcohol)
  
• acetylene (the fuel used in welding torches)
  
• ammonia

Cigarette smoke also contains the poisonous gases nitrogen oxide and carbon monoxide. Its main active ingredient is nicotine, an addictive drug.

 "Smoker's cough"

Cigarette smoke contains chemicals that irritate the air passages and lungs.
When a smoker inhales these substances, the body tries to protect itself by
producing mucus and coughing. The "early morning" cough of smokers happens for
several reasons. Normally, tiny hairlike formations (called cilia) beat outward
and sweep harmful material out of the lungs. Cigarette smoke slows the sweeping
action, so some of the poisons in the smoke remain in the lungs and mucus remains
in the airways. When a smoker sleeps, some cilia recover and begin working again.
After waking up, the smoker coughs because the lungs are trying to clear away
the poisons that built up the previous day. The cilia stop working after long-term
exposure to smoke. Then the smoker's lungs are even more exposed and susceptible
than before, especially to bacteria and viruses in the air.

Wherever smoke touches living cells, it does harm. Even if smokers don't inhale they are breathing the smoke as secondhand smoke and are still at risk for lung cancer. Pipe and cigar smokers are also at an increased risk for lip, mouth, and tongue cancers.

Tobacco causes Cancer

Tobacco use accounts for about one-third of all cancer deaths in the United States. Smoking causes almost 90% of lung cancers. Smoking also causescancers of the larynx (voice box), oral cavity, pharynx (throat), and esophagus, and contributes to the development of cancers of the bladder, pancreas, liver, uterine cervix, kidney, stomach, colon and rectum, and some leukemias.

Effect on Lungs

All cigarette smokers have a lower level of lung function than nonsmokers. Cigarette smoking causes several lung diseases that can be just as dangerous as lung cancer. Chronic bronchitis - a disease where the airways produce excess mucus, which forces the smoker to cough more often - is a common ailment of smokers.

Cigarette smoking is also the major cause of emphysema - a disease that slowly destroys a person's ability to breathe. For oxygen to reach the blood, it must move across large surfaces in the lungs. Normally, thousands of tiny sacs make up the surface area in the lungs. When emphysema occurs, the walls between the sacs break down and create larger but fewer sacs. This decreases the amount of oxygen reaching the blood. Eventually, the lung surface area can become so small that a person with emphysema has to often gasp for breath, with an oxygen bottle nearby or with oxygen tubes inserted into the nose.

More than 7 million current and former smokerssuffer from chronic obstructive pulmonary disease (COPD), the name used to describe both chronic bronchitis and emphysema. Often both of these conditions are present in one person.

 Effect on the heart

Smoking cigarettes increases the risk of heart disease, which is America's number one cause of death. Smoking, high blood pressure, high blood cholesterol, physical inactivity, obesity, and diabetes are all risk factors for heart disease, but cigarette smoking is the biggest risk factor for sudden heart death. Also, smokers who have a heart attack are more likely to die within an hour of the heart attack than nonsmokers.

 Effect on pregnant women and their babies

Pregnant women who smoke risk the health and lives of their unborn babies. Smoking during pregnancy is linked with a greater chance of spontaneous abortions, stillbirths, infant deaths, and sudden infant death syndrome (SIDS). Up to 10% of infant deaths could be prevented if pregnant women did not smoke.

When a pregnant woman smokes, she's smoking for two. The nicotine, carbon monoxide and other harmful chemicals enter her bloodstream, pass directly into the baby's body, and prevent the baby from getting essential nutrients and oxygen for growth.

 Short- and long-term effects of smoking

Smoking causes many types of cancer, which may not develop for years. The truth is cigarette smokers die younger than nonsmokers. In fact, according to a Centers for Disease Control (CDC) study conducted in the late 1990s,smoking shortened male smokers'lives by 13.2 years and female smokers' lives by 14.5 years. Both men and women who smoke are much more likely to die during middle age (between the ages of 35 and 69) compared to those who have never smoked.

There are many more short-term effects of smoking. A major consequence of smoking is decreased lung function. Because of this smokers often suffer from shortness of breath, nagging coughing, or tiring easily during strenuous physical activity. Smoking also diminishes the ability to smell and taste and causes premature aging of skin.

 Quitting smoking

Quitting smoking is not easy, and some people try several times before succeeding. Many of those who have tried to quit have done so on their own by either stopping "cold turkey," participating in the Great American Smokeout®, or using other methods.

There's no one right way to quit. Quitting for good may mean using many methods including using step-by-step manuals, self-help classes or counseling, or using a nicotine replacement therapy (see next question). Smokers may also need to make changes in their daily routine to help them not smoke.

Nicotine replacement therapy

Nicotine replacement therapies are medications that provide nicotine without the other harmful components of cigarette smoke. NRTs are available as patches, gums, inhalers, nasal sprays, or lozenges to help decrease or stop a smoker's withdrawal symptoms. The US Food and Drug Administration (FDA) have approved all of these products as smoking cessation aids, although some require a doctor's prescription. These products should be used with behavior change programs to help smokers break their psychological dependence on cigarettes.

Not everyone can use nicotine replacement therapy. People with certain medical conditions and pregnant women should not use it. When using the patch, it's very important that users do not smoke cigarettes or use tobacco in any form.

Another medication, bupropion (Zyban) is also FDA approved for helping people quit smoking. This medication, which does not contain nicotine, is available with a doctor's prescription.

Can quitting really help a lifelong smoker?

It is never too late to quit. The sooner smokers quit, the more they can reduce their chances of getting cancer and other diseases. Within 20 minutes of smoking the last cigarette, the body begins to restore itself.

• After 20 minutes: Your blood pressure drops to a level close to that before the last cigarette. The temperature of your hands and feet increases to normal.
  
• After 8 hours: The carbon monoxide level in your blood drops to normal.
  
• After 24 hours: Your chance of a heart attack decreases.
  
• Within 3 months: Your circulation improves and your lung function increases up to 30%.
  
• In 1 to 9 months: Coughing, sinus congestion, fatigue, and shortness of breath decrease; cilia (tiny hair like structures that move mucus out of the lungs) regain normal function in the lungs, increasing the ability to handle mucus, clean the lungs, and reduce infection
  
• After 1 year: The excess risk of coronary heart disease is half that of a smoker's.
  
• After 5: Your stroke risk is reduced to that of a nonsmoker.
  
• After 10 years: The lung cancer death rate is about half that of a continuing smoker's. The risk of cancer of the mouth, throat, esophagus, bladder, kidney, and pancreas decreases
  
• After 15 years: The risk of coronary heart disease is that of a nonsmoker's.

It's important to note that the extent to which these risks decrease depends on how much the person smoked, the age the person started smoking and the amount of inhalation.

Based on current smoking patterns, smoking will kill about 500 million people
alive in the world today. Tobacco-caused deaths worldwide are expected to increase
from about 4 million per year today to about 10 million per year by the 2030s.
Most of these deaths will occur in developing countries.

In the US, tobacco causes nearly 1 in 5 deaths, killing more than 440,000 Americans each year. Smoking is the single most preventable cause of death in our society.

The tobacco industry is one of the most profitable businesses in the country,
making billions of dollars yearly. But the costs of smoking are far higher than
the income from cigarette sales.

• Smoking causes more than $150 billion each year in health-related costs, including the cost of lost productivity due to smoking.
  
• Smoking-related medical costs totaled more than $75 billion in 1998 and accounted for 8% of personal health care medical expenditures.
  
• Death-related productivity losses due to smoking among workers cost the U.S. economy more than $81 billion (average for 1995-1999).
  
• For each pack of cigarettes sold in 1999, $3.45 was spent on medical care due to smoking, plus $3.73 in lost productivity, for a total cost of $7.18 per pack.

Gene and its role

The principal component thought to be involved in addiction to tobacco use is nicotine. Each cigarette contains a total of 1–3 mg of nicotine and users chew, sniff, or smoke tobacco to maximize the absorption of nicotine through mucus membranes. The effects of smoking are complex, and therefore, gaining an understanding of how nicotine affects human cell function may be essential in developing rational methods for treating tobacco dependence. It has been suggested that a high frequency of relapse to the smoking habit following smoking cessation treatment occurs during the first 6 months after quitting, and that a higher degree of nicotine dependence is correlated with shorter time to relapse.

Seven genes, designated œ2,œ 3,œ œ4,œ œ5, œ6,
œ7, and œ9 and an eighth, œ10, that are homologous to the ligand
binding subunit (œ 1) of muscle type nicotine receptors, have been cloned
from rat brain and sequenced. A second set of genes, ß2, ß3, and
ß4, have also been cloned and sequenced from rodents. Human homologs have
been cloned for œ2, œ3, œ4, œ6, œ7, ß2, ß3,
and ß4. All have a high degree of homology with the corresponding rat
genes.

Expression of nicotinic receptor subunits is generally low in human brain,
compared to other ligand-gated ion channels, and varies across brain regions
with the most abundant subunit,œ 4, being highly expressed in human thalamus
and cortex and œ7 in human hippocampus, lateral and medial geniculates,
and the reticular thalamic nucleus. The actual composition of native nAChR,
in either the brain or in the periphery, has not been fully defined. The assembly
of nAChR may be specific for each cell within a given tissue, and dependent
upon relative subunit expression.

One of the more interesting forms of regulation for the neuronal nicotinic receptor gene family is the paradoxical up-regulation seen in subjects chronically treated with nicotine. Chronic nicotine infusion in mice results in a dose-dependent and time-dependent tolerance to nicotine that is paralleled by dose-dependent increases in both [³H]nicotine and [¹²⁵I] -bungarotoxin binding, suggesting that both high and low affinity receptors are affected. Many other studies have replicated the increases in nicotinic receptor levels in rats, treated chronically with nicotine

In humans, far less is known about the relationship between nicotine abuse and receptor levels. Several studies suggest that brain tissues from smokers have more [³H]nicotine binding than is seen in non-smokers. It has been found that the number of [³H]nicotine binding sites is correlated with the number of cigarettes smoked per day. In the brains of smokers who had quit smoking for different periods of time before death, binding levels had returned to the normal range, suggesting that monitoring nicotinic receptor levels during smoking cessation might provide valuable information regarding responses to smoking cessation and relapse. However, in postmortem brain it is not possible to examine a time course for receptor decreases following cessation of smoking. Development of a receptor assay in a tissue that could be measured in live subjects seemed necessary. In peripheral blood lymphocytes and PMN there has been one study showing that nicotinic receptors are increased in smokers and decline when subjects stop smoking.

Dose response of nicotinic receptor levels was not reported. In our present
study, we have compared [³H]nicotine binding in peripheral blood
PMN with smoking levels in human subjects. PMN were used for the assay development
rather than lymphocytes because PMN are more abundant and less blood would,
therefore, are required from each subject. High affinity nicotinic receptor
numbers, measured by [³H]nicotine binding, were increased in smokers
in a dose-dependent manner. We also examined expression of mRNA and protein
for a subset of the nicotinic receptor subunits, finding that the receptor population
is likely to be partially composed of œ4 œ2, œ3 œ4 and œ7
receptors in lymphocytes and œ3 ß4 in PMN.

Polymorphisms of the CYP2A6 gene

The cytochromes P450 are a superfamily of enzymes involved in the metabolism of numerous exogenous and endogenous substances including drugs, environmental chemicals, steroid hormones and bile acids. Many of the genes that encode the drug metabolising P450s are to a high extent polymorphic, thereby causing pronounced interindividual variability in the metabolism of many clinically used drugs.

Cytochrome P450 2A6 (CYP2A6) is a hepatic P450, which metabolises certain pharmaceutical agents, e.g. coumarin, (+)-cis-3,5-dimethyl-2-(3-pyridyl) thiozolidin-4-one hydrochloride (SM-12502), methoxyflurane, halothane, losigamone, letrozole, valproic acid and disulfiram. The enzyme can also activate a number of precarcinogens, including 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK), N-nitrosodiethylamine, 1,3-butadiene and 2,6-dichlorobenzonitrile. In humans, the major pathway for nicotine metabolism consists of its C-oxidation to cotinine followed by cotinine 3′-hydroxylation, with CYP2A6 being the major enzyme that catalyses both of these reactions.

Phenotyping studies done with the probe drug coumarin have revealed pronounced interindividual variability in CYP2A6 activity in vivo. Similar results have been obtained when CYP2A6 levels and activity were determined in human liver microsomes. Despite the great interindividual variation observed, very few individuals lacking CYP2A6 activity have been found in Caucasians. The frequency of poor metabolisers (PMs) in European and Middle East populations is ≤1%, whereas it is much higher in Asian populations.

Genetic polymorphisms of the CYP2A6 gene can probably explain this interindividual
variability to a great extent. Two types of defective alleles have been described
thus far. The CYP2A6*2
allele encodes an enzyme with a L160H substitution that does not incorporate
haem and is therefore inactive. It has also been described some inactive alleles
common in Asian populations where parts of or the whole CYP2A6 gene has
been deleted (CYP2A6*4A, *4B and *4C). In addition, CYP2A6*3,
described as a hybrid allele generated by multiple gene conversions with the
inactive CYP2A7 gene, has been proposed to be inactive but this has not
yet been demonstrated.

Is it really in genes

A new study out of Canada suggests young people are more likely to become addicted to cigarettes if they carry a specific form of a gene that helps clear nicotine out of the liver. Those with the inactive form of the CYP2A6 gene were about three-times more likely to get hooked on the habit than those with the normal form.

The interesting thing is they were also less likely to smoke as many cigarettes. In the study, which was carried out among seventh graders in 10 schools, kids with the normal gene averaged about 29 cigarettes a week, compared to just 12 for kids with the inactive form of the gene. Kids with a partially inactive version of the gene smoked about 17 cigarettes a week.

The investigators believe the inactive gene causes nicotine to stay in the
body longer, thus requiring people to smoke fewer cigarettes in order to satisfy
their cravings. Understanding the role genetics may play in getting children
hooked on tobacco is important for public health policy. Genetic risk for (nicotine
dependence) should be taken into account in the conceptualization of prevention
and cessation programs for adolescents.

Nicotine gene & smoking behavior

Many of the forbidden pleasures of the modern day-nicotine, alcohol and over-eating- appear to be linked by common genetic factors. Genetic variables appear to play a key role in every aspect of nicotine addiction, from the tendency to begin smoking, to the chances of quitting.

Evidence is now converging from behavioral studies, twin studies and molecular
genetic research that provides a clear understanding of the bio-behavioral basis
for nicotine dependence. Ultimately this should lead to the development of improved
methods for assessment and treatment of dependence.

Behavioral scientists have made progress in defining the phenotype and carefully pointing out the variables that have to be taken into account in describing individual differences in smoking behaviors. Molecular biologists have made great progress in identifying an array of nicotinic receptors, the genes involved and their locations, and other neurochemicals (particularly dopamine) that may be involved in regulation and activation of nicotine related behavior.

A study analyzed more than 20 studies of smoking behaviors in monozygotic and
dizygotic twins. They found consistent evidence of genetic influences governing
the developmental stages of smoking (initiation, maintenance, cessation), smoking
intensity (light to heavy), as well as for level alcohol consumption.

The discovery of a gene that appeared to be associated with alcoholism, the
D2 dopamine receptor gene (DRD2). Since that time further studies implicating
this gene in behaviors associated with tobacco, cocaine and obesity were done.

There are two main dopaminergic pathways in brain. The first begins in the
area called the substantia nigra and is involved with movement. Defects in this
part of the brain are associated with movement disorders such as Parkinson's
disease. The second pathway, the mesolimbic dopamine system, is associated with
emotion activation.

The DRD2 gene is found on chromosome 11, in the q22-23 region. There are two
alleles of interest, A1 found in 25% of the population and A2 found in 75%.
Studies comparing alcoholics to controls showed a significantly higher incidence
of A1 allele. The A1 allele is associated with significantly reduced levels
of D2 dopamine receptors in the brain. This led to the hypothesis that individuals
with the A1 allele may have an inherent deficit of the dopaminergic system.
To compensate for that deficiency, they are high risk for using alcohol, and
other substances which by releasing dopamine activate these areas.

Recently a study was completed of the association between this gene with smoking
and obesity. This study showed that male, but not female, smokers with the A1
allele began to smoke at an earlier age than those with the A2 allele. Also,
the female smokers with the A1 allele were less likely to be obese, while male
smokers with the A1 allele were more likely to be obese. The study also showed
that non-obese female smokers with the A1 allele had higher levels of anxiety
and depression, while obese female smokers had lower anxiety scores. These studies
add further support for the role of this gene in weight and mood in smokers
and non-smokers. However, the differences seen in males and females suggest
that besides DRD2 gene, other epigenetic and environmental factors play a role
in contributing to these gender differences.

These findings could point the way to useful therapies for those attempting
to quit smoking or drinking. A recent study with bromocriptine, a drug that
increases levels of DRD2, showed significant improvements in craving and anxiety
among alcoholics trying to quit.

Many individuals fall into this category of smokers—people who just can’t seem to butt out. For these people, the inability to quit is proving to be more a product of genetics than a weakness of character or lack of motivation.

It has long been known that nicotine is the culprit in establishing and maintaining
tobacco addiction. However, the rate at which one smoker metabolizes nicotine
compared with another separates those who become heavily dependent on cigarettes
from those who remain social smokers.

The key player appears to be a liver enzyme called CYP2A6, which is a member
of the cytochrome P-450 family of proteins. CYP2A6 governs the metabolism of
nicotine to cotinine in a two-step process (see Figure 1). Three versions of
the gene encoding CYP2A6 have been identified in various populations: one normal,
or wild-type, version and two that are functionally impaired. The wild-type
enzyme actively metabolizes nicotine, clearing it rapidly from the body. Thus,
a smoker needs to light up frequently to maintain blood and brain nicotine levels
and keep withdrawal symptoms at bay. However, CYP2A6 is a double-edged sword
in that it also activates procarcinogens found in tobacco smoke into bona fide
carcinogens.

For individuals with a defective copy of the gene, however, nicotine metabolism
is impaired, and the smoker is protected from heavy dependency. As a result,
smokers with the defective gene are less likely to take up the habit. They smoke
less even if they do become dependent, and they are less likely to develop smoking-related
cancers and medical conditions because procarcinogen activation is believed
to be less likely to occur.

Cessation assistance

It has been found that an inhibitor that can gum up the activity of CYP2A6 and help heavily dependent smokers get a handle on their addiction. “Nicotine leaves the body rapidly, which is why heavy smokers light up every hour—to fill up their nicotine tank. If you don’t metabolize it very well due to lack of enzyme, nicotine enters the body and stays there for a long time.

After screening more than 200 compoundsit was found that methoxsalen, a medication
already approved for treating psoriasis, was an effective inhibitor of CYP2A6
activity. In one study, 17 smokers who were not intending to quit were given
tablets containing 30, 10, or 3.5 mg of methoxsalen or a placebo orally, along
with a 4-mg nicotine tablet. Blood nicotine levels were measured at 30-min intervals
over 3 h. As expected, those who received the higher doses of methoxsalen had
nicotine levels that were twice as high as those who took the 3.5-mg methoxsalen
or placebo tablets, and they reported they did not feel the urge to light up
as often.

In a second study, smokers were given either 30-mg methoxsalen tablets or a
placebo, along with a nicotine tablet or a placebo, and were made to abstain
for 1 h. They were then permitted to smoke to their hearts’ content for 90 min.
Again, those who received the inhibitor smoked fewer cigarettes and took fewer
puffs.

If we gave oral nicotine and the inhibitor, smoking decreased by 50. In those
who received the inhibitor alone [and received a placebo tablet instead of the
nicotine tablet], smoking decreased 30%.

As a drug delivery system, cigarettes deliver nicotine to the brain faster
than any intravenous system. As nicotine enters their body, smokers experience
an immediate spike of the drug, followed by a drop as it is converted to cotinine.
Nicotine patches, sprays, and gum, in contrast, provide a steady source of nicotine
that does not mimic the spikes to which the smoker has become accustomed. The
use of an inhibitor on its own could, at the very least, decrease smoking frequency
by helping to maintain nicotine levels in the body for longer periods. Smokers
who use an inhibitor together with other replacement therapies may find it easier
to stick to treatment and learn behavior modification techniques.

While nicotine is generally regarded as relatively harmless, the carbon monoxide,
tars, nitrosamines, free radicals, and thousands of other chemicals—not to mention
30 known carcinogens—found in cigarettes make smoking a health hazard unlike
any other.

Changing behavior

Undoing that addiction is another matter entirely. Current cessation therapies
work well for some and not for others because of huge variations in blood nicotine
levels. Giving an inhibitor to people to slow down nicotine metabolism makes
a diverse population now quite similar. With blood nicotine levels maintained
and the burning desire to light up quenched, smoking cessation therapies have
a greater likelihood of success. Even those who do not quit might, at the very
least, scale back the number of cigarettes they smoke each day. An inhibitor
will be of enormous help to some individuals, pointing out that for some smokers,
structural changes that occur in the brain in response to nicotine do not necessarily
return to normal. Furthermore, nicotine is a structural mimic of the neurotransmitter
acetylcholine, binding to its receptors in the brain.

Conclusion

A whole cascade of neural transmitters, which leads to a number of [systemic] effects that nicotine increases metabolism by 5% to 8%, lessens irritability, improves mood, and enhances concentration. Consequently, when smokers quit, they are faced with a nervous system redesigned for nicotine and are unable to function well without the drug. Cigarette manufacturers are currently developing cigarettes that distill nicotine rather than burn tobacco and its harmful constituents. Like it or not, nicotine addiction won’t ever go away.

Longer-term studies in the pipeline are looking at the safety and efficacy
of methoxsalen and other potent inhibitors have found. For those who cannot
seem to kick the habit, this may be their best hope.

References

1. Pianezza, M. L.; Sellers, E. M.; Tyndale, R. F. Nature 2000, 393, 750.
   
2. Sellers, E. M.; Kaplan, H. L.; Tyndale, R. F. Clin. Pharmacol. Ther. 2000,
   68, 35–43.
   
3. [³H]Nicotine binding in peripheral blood cells of smokers is
   correlated with the number of cigarettes smoked per day, Khalid Benhammou,
   Michael Lee, MaryAnn Strook, Bernadette Sullivan, Judith Logel, Kristie Raschen,
   Cecilia Gotti and Sherry Leonard, Neuropharmacology, Volume 39, Issue 13,
   December 2000, Pages 2818-2829
   
4. Identification and characterisation of novel polymorphisms in the CYP2A
   locus: implications for nicotine metabolism, Mikael Oscarson, Roman A. McLellan,
   Harriet Gullstén , José A. G. Agúndez, Julio Benítez, Arja Rautio, Hannu Raunio,
   Olavi Pelkonen and Magnus Ingelman-Sundberg Federation of European Biochemical
   Societies. Volume 460, Issue 2, 29 October 1999, Pages 321-327
   
5. M. Ingelman-Sundberg, M. Oscarson and R.A. McLellan. Trends Pharmacol.
   Sci. 20 (1999), pp. 342–349.
   
6. A. Rautio, H. Kraul, A. Kojo, E. Salmela and O. Pelkonen. Pharmacogenetics
   2 (1992), pp. 227–233.
   
7. S. Cholerton, M.E. Idle, A. Vas, F.J. Gonzalez and J.R. Idle. J. Chromatogr.
   575 (1992), pp. 325–330.
   
8. S. Yamano, J. Tatsuno and F.J. Gonzalez. Biochemistry 29
   (1990), pp. 1322–1329.
   
9. G. Truan, C. Cullin, P. Reisdorf, P. Urban and D. Pompon. Gene 125
   (1993), pp. 49–55
   
10. Nakajima, M.; Yamamoto, T.; Nunoya, K.; Yokoi, T.; Nagashima, K.; Inoue,
    K.; Funae, Y.; Shimada, N.; Kamataki, T.; Kuroiwa, Y. : Role of human cytochrome
    P4502A6 in C-oxidation of nicotine. Drug Metab. Dispos. 24: 1212-1217, 1996.
    
11. Sabol, S. Z.; Hamer, D. H. : An improved assay shows no association between
    the CYP2A6 gene and cigarette smoking behavior. Behav. Genet. 29: 257-261,
    1999.
    
12. O.H. Lowry, N.J. Rosebrough, A.L. Farr and R.J. Randall. J. Biol. Chem.
    193 (1951), pp. 265–275.
    
13. T. Omura and R. Sato. J. Biol. Chem. 239 (1964),
    pp. 2370–2378.
    
14. A. Aitio. Anal. Biochem. 85 (1978), pp. 488–491
    
15. London, S. J.; Idle, J. R.; Daly, A. K.; Coetzee, G. A. : Genetic variation
    of CYP2A6, smoking, and risk of cancer. Lancet 353: 898-899, 1999.

About Authors

Madhumathi Seshadri^b, Neha Shah^c and Mrs. Lakshmi
Sivasubramaniam ^a, *

^{* a} Lecturer, Department of Pharmaceutical Analysis, College of
Pharmacy, SRM Institute of Science and Technology

^b  Department of Chemistry, Pharmaceutical Chemistry unit,
Vellore Institute of Technology,Vellore-632 014, India

^c Bio medical Genetics, Department of Bio sciences, Vellore Institute
of Technology,Vellore-632 014, India

*^,a Author for Correspondence: Lakshmi Sivasubramaniam,
Lecturer, Department of Pharmaceutical Analysis, College of Pharmacy, SRM Institute
of Science and Technology, Deemed University, Katangulathur, Chennai, India

E-mail : laxmisiva@rediffmail.com