23 November 2015

Smoking at the molecular level

We don't want nicotine, or briefly and succinctly about smoking

Fedor Galkin, "Biomolecule" 

The impact of tobacco smoking on human health is a favorite topic of journalists. There are thousands of brochures, articles and books about how harmful smoking is and how to get rid of nicotine addiction. As a rule, their authors limit themselves to considering the psychological aspect or focus the reader's attention exclusively on the severe medical consequences of smoking. And, as a rule, no one describes the mechanism of nicotine addiction or the interaction of tobacco with the body at the molecular level. This article attempts to eliminate this lack of literature on smoking.

Van Gogh often used tobacco as a substitute for food when there was not enough money. The ability of nicotine to dull hunger is explained by its effect on the hunger center in the hypothalamus [1].

Tobacco yesterday and todayEveryone knows that the American Indians taught Europeans to use tobacco.

Shortly after the expeditions of Columbus at the end of the XV century, the Spaniards began to cultivate tobacco. Tobacco owes its scientific name (Latin Nicotiana) to the French ambassador to Portugal, Jacques Nicot, a well–known popularizer of tobacco products in the second half of the XVI century. Niko's authority was so great that tobacco quickly began to be used not only for entertainment purposes, but also in medical practice. So, in 1571, the Spanish doctor Nicolas Monardes wrote a book about medicinal plants, in which he claimed that tobacco cures 36 diseases [2].

The fight against tobacco smoking began in the XVII century. The English King James I was one of the first to pursue an anti-smoking policy. In the treatise "Protest to tobacco" ("A counterblaste to tobacco") of 1604, he calls tobacco smoking "a custom that is disgusting in appearance, disgusting in smell, harmful to the brain and dangerous to the lungs." The tract was followed by a 40-fold increase in tobacco duties. In the Ottoman Empire, smoking was banned in 1633 by decree of Sultan Murad IV and was punishable by death, but soon the ban was replaced by a tax. In pre-Petrine Russia, smokers were beaten and even exiled or executed. In many other European and Asian countries, there have been obstacles to the spread of tobacco for quite a long time [3, 4].

In 1828, scientists from Heidelberg isolated nicotine in its pure form and concluded that it was a strong poison. Soon after, nicotine was used as an insecticide. At about the same time, cigarettes appear, while inferior in popularity to cigars. Despite the global spread of tobacco, tobacco smoking has not yet been recognized as a global problem. So, by 1889, only 140 cases of lung cancer were documented worldwide. In the same year, the English physiologist John Newport Langley describes the effect of nicotine on the conduction of nerve ganglia: nicotine blocked the transmission of impulses in the sympathetic nervous system [5].

At the beginning of the XX century, cigarettes became the main tobacco product, and the largest tobacco companies in the world are based in the USA. In 1912, oncologist Isaac Adler for the first time indicates a link between smoking and lung cancer. Lung cancer remained a rare disease until the First World War, after which smoking became a ubiquitous habit due to the inclusion of cigarettes in the army diet.

In the 1930s, the link between smoking and lung cancer, as well as a reduction in life expectancy, was strictly proven. Nevertheless, the popularity of tobacco continued to grow at an unprecedented rate. It was only in the 1980s that the existence of nicotine addiction was internationally recognized, followed by restrictions on advertising and distribution of tobacco products. It was since the 1980s that healthcare structures around the world began to fight tobacco smoking, despite which, the tobacco industry is still thriving and annually increasing its turnover.

Mechanism of nicotine addiction formationTobacco definitely wouldn't have become so popular if it didn't cause addiction.

However, the mechanism of nicotine's effect on the nervous system has become known relatively recently. To understand this mechanism, it is necessary first of all to know how the transmission of nerve impulses occurs.

Neurons, as a result of the energy–dependent withdrawal of three Na+ ions from the cell in exchange for the input of two K+ ions, create an electrochemical gradient on their membrane [6] – the cell is polarized (positive charge accumulates inside, and negative charge accumulates outside). When the cell is stimulated, depolarization occurs: channels open in the cell membrane that equalize Na+ concentrations on both sides of it. Opening channels in one place triggers chain depolarization throughout the cell. If the sodium channels remained open, the neuron would be constantly in a depolarized state. However, this does not happen, because sodium channels open only for a few milliseconds, and after them other channels open, removing K+ from cells, which contributes to repolarization. The undulating opening of sodium and potassium channels is called the action potential (PD).

PD transmission from one neuron to another differs from intracellular transmission. When the PD reaches the contact of two neurons, the excited cell receives not Na+, but a lot of Ca2+ ions, which are a signal for the release of neurotransmitters into the intercellular gap* 

* – The story related to the transport and secretion of neurotransmitters in nerve fibers is exciting and beautiful. In 2013, the Nobel Prize was awarded for its study [7], and already in 2015, a stunning comic depicting these processes appeared on biomolecule: "How the neurotransmitter is isolated" [8]. – Ed.

Neurotransmitters, binding to ion channels (receptors) on the membrane of the receiving cell, trigger PD in it. Nicotine is structurally similar to one of the most common neurotransmitters in the body – acetylcholine (Ach) – and mimics its action, which is why some cellular Ach receptors have become called nicotine [9].

Figure 1. Signal transmission scheme in neurons. a – designations on the diagram, b – the actual diagram. At rest, a neuron with an energy expenditure creates tension on its membrane. Under external influence, the neuron depolarizes, which leads to the release of neurotransmitters (green circles) that trigger depolarization in the next neuron. Depolarization is necessarily followed by repolarization, which returns the cell to its original state.When the body relies on nicotine coming from outside instead of Ach, dependence arises.

More precisely, the substitution of Ach in the tegmentum, also known as the pleasure center, leads to the formation of nicotine addiction. With a natural concentration of Ach, arousal and suppression of the pleasure center are balanced.

But with regular use of nicotine, neurons adapt: there are fewer nicotine receptors in synapses, leading to the suppression of the tegmentum (α4β2), when the number of receptors leading to its activation (α7) remains the same. It is also worth considering that nicotine is very stable and therefore leads to a much longer stimulation of the pleasure center than Ach, which decomposes in synapses in a matter of milliseconds.

Stimulation of the tegmentum is a key moment in the formation of various kinds of addictions and behavior in general. But the pleasant sensations caused by nicotine are only one side of the coin. Do not forget about the withdrawal syndrome, because of which most smokers who decide to quit, break down again and again.

Withdrawal syndrome consists of loss of concentration, anxiety, depression, insomnia and increased appetite when refusing to use nicotine. You can often hear that cigarettes help to cope with stress, but stress and withdrawal syndrome are very similar in terms of physiology, which makes you doubt the soothing properties of nicotine. At the moment, it is not known exactly how the elimination of nicotine from the body leads to withdrawal syndrome. Nevertheless, it is clear that an important role in its occurrence is played by the center of discontent – the habenula, which suppresses the tegmentum when we do not get what we want. The work of this part of the brain also strongly depends on nicotine receptors, and most likely, neuroadaptation also occurs in it, leading to unpleasant sensations with a lack of nicotine [10].

Figure 2. The formation of nicotine addiction. Normally, the neurotransmitter acetylcholine (Ach) maintains a balance of stimulation and suppression of the pleasure center (tegmentum). Nicotine causes pleasant sensations due to the binding of α7- and a decrease in the number of α4ß2-receptors. When the nicotine level drops, another part of the brain – the habenula – suppresses the pleasure center. These two phenomena lead to the formation of nicotine addiction.Physiological effects of nicotine

Nicotine can be consumed in many ways, but cigarette smoking is the most common.

During smoking, most of the nicotine burns in flames, but a small amount of inhaled nicotine is compensated by the giant surface of the lungs through which it is absorbed into the blood. When using chewing tobacco, nicotine concentrations in saliva are up to 6 orders of magnitude higher than the concentration in lung fluids after one cigarette.

Nicotine that has entered the body in one way or another stimulates nicotine receptors not only in the brain, but also in all other tissues. In the lungs, nicotine stimulates the division of mucosal cells by activating the corresponding receptor. Excessive division combined with DNA damage caused by tobacco carcinogens can lead to lung carcinoma. Similar phenomena are observed in cells throughout the body, which is why nicotine consumption (even not through smoking) increases the risk of breast, uterine and food tract cancer.

The effect of tobacco smoke and nicotine on the immune system is extremely interesting and ambiguous. Depending on the frequency, smoking experience and individual differences, tobacco smoke (TD) can both stimulate and suppress immunity. For example, TD is rich in active oxygen forms that cause chronic lung inflammation, that is, it generally stimulates the immune system. And although some studies have shown that TD activates immune T-cells, this does not mean that tobacco is useful for immunity: medical statistics say that smokers suffer more often and more seriously from colds, pneumonia and tuberculosis than non-smokers [11]. In addition, in other studies, where more attention is paid to antiviral immunity, it has been shown that TD reduces the body's resistance to viruses [12].

Smoking also affects the course of autoimmune diseases [13]. It is known that smoking aggravates rheumatoid arthritis, Crohn's disease (but relieves ulcerative colitis!) [14] and contributes to the development of emphysema of the lungs. Relatively recently, people began to understand the reasons for this: activated T cells begin to produce antibodies to the structural protein of the lungs, arteries and skin - elastin [15]. Such antibodies target the smoker's immunity to his own body. The autoimmune aspect is one example of the irreversible effects of TD on health, since once formed antibodies will continue to be synthesized even years after quitting smoking.

You can often hear that smoking leads to diseases of the cardiovascular system. In many ways, these diseases are provoked by the factors already mentioned: oxidative stress and inflammation.

Reactive oxygen species TD reduce the activity of the enzyme responsible for vascular relaxation and pressure reduction – NO-synthase. This enzyme produces nitric oxide NO, which, when reacting with reactive oxygen species, turns into a toxic peroxynitrite molecule [16]. Thus, by reducing the NO level, smoking leads to hypertension – the main cause of ischemic diseases. Smoking causes impotence by the same mechanism: lack of NO leads to vasoconstriction and a decrease in blood flow in all organs.

Another problem that only male smokers can face is the loss of the male Y chromosome. Swedish scientists have found that the blood of smokers contains 3-4 times more cells that have lost this purely male part of the genome. This phenomenon may be associated with general genetic instability caused by tobacco smoke mutagens, and very likely contributes to the development of cancer [17].

Chronic lung inflammation in smokers activates white blood cells throughout the body, including in the blood. Against the background of this inflammation, there is a decrease in the number of endothelial progenitor cells that provide restoration of damaged vessels [18], and blood clotting increases [19].

Modern means of combating nicotine addictionIn developed countries, every year half of smokers try to quit their bad habit, but only 2% of them succeed.

Such a low success rate is due to the fact that smokers usually decide to quit suddenly and try to do it without resorting to auxiliary means.

The most popular way to treat nicotine addiction is nicotine replacement therapy (NRT). It is based on the idea that taking nicotine in controlled and constantly decreasing doses ultimately leads to getting rid of addiction. The first preparation of NRT was a nicotine chewing gum, released in 1971 by the Swedish company Nicorette. Today, pharmacies sell dozens of drugs from different companies based on the "wedge by wedge" principle: nicotine patches, inhalers, lollipops, sprays and, of course, chewing gum. A number of studies have shown that NRT is twice as effective as using a placebo [20], and would help to quit another three percent of smokers.

Much less well-known are other, sometimes much more effective, smoking medications.One of these drugs is cytisine– an alkaloid of broom.

This plant has been known to traditional medicine for centuries, and during the Second World War, people began to consider it as a substitute for tobacco. Cytisine appeared on the market even earlier than nicotine gum – in 1964 it began to be produced in Bulgaria under the brand name Tabex.

Cytisine, like nicotine, can bind to nicotine receptors in the brain. But, firstly, it binds to them more strongly, that is, it does not allow nicotine to reach them, and secondly, it activates them weaker. Thus, cytisine interferes with the reinforcement of addiction, even if a person continues to consume nicotine. If a person has stopped smoking and is experiencing discomfort, then cytisine stimulates the pleasure center enough to eliminate the withdrawal syndrome, but not enough to form a new addiction.

This drug has not been widely used outside of Central and Eastern Europe [21]. According to 2011 data, cytisine is 3.5 times more effective than nicotine replacement therapy drugs [22]. However, it is worth considering that fewer studies have been conducted on cytisine as a whole than on other drugs, which actually prevents its spread in the world.

A similar mechanism of action has varenicline – a drug of the largest pharmaceutical corporation Pfizer, produced since 2006. Varenicline has passed rigorous clinical trials and is sold worldwide. Its effectiveness in long-term therapy is slightly greater than that of NRT, while the drug itself is noticeably more expensive than nicotine gum and cytisine [23].

Another common remedy for nicotine addiction is bupropion. This drug has been produced since 1989 and is positioned primarily as an antidepressant. Its ability to facilitate smoking cessation is only a side effect: bupropion binds nicotine receptors in the brain, but does not activate them. In terms of effectiveness, this substance is comparable to nicotine replacement therapy [24].

Figure 3. Nicotine is chemically similar to acetylcholine (one of the substances that ensure the transmission of nerve impulses between neurons) and mimics its action. Modern drugs for nicotine addiction are structurally similar to nicotine, but have a different effect on nicotine receptors of neurons, facilitating withdrawal syndrome.The action of all the described drugs is based on the binding of nicotine receptors in the brain.

In recent years, we have been actively developing a fundamentally different approach to the treatment of nicotine addiction – vaccination against nicotine.

As with conventional vaccination, antibodies are formed in the patient's body during this therapy. Antibodies bind nicotine, thereby preventing it from entering the brain and depriving it of physiological activity.

Vaccines of this kind can help not only from nicotine, but also from any other chemical dependence (except alcohol). Usually the body does not produce antibodies against small molecules of psychoactive substances, so in vaccines these molecules are combined with larger proteins, which cause an immune reaction.

Successful trials of nicotine, methamphetamine, cocaine and opiate vaccines have already been conducted. With vaccination, the side effects of treatment are much weaker, and the effect is more stable than with drug therapy. But there are drawbacks: vaccination does not work at all on a quarter of addicts. In addition, anti-nicotine vaccination can scare off with its duration: the course consists of 4-5 injections for three months [25].

Recently, the genetic approach to nicotine addiction research has become extremely popular. Thanks to mass studies of the genome of smokers, thousands of mutations have already been identified that affect the likelihood of starting or quitting smoking and determine the severity of nicotine addiction. The data obtained can help in the creation of new means for quitting smoking or help to choose the most effective of the existing ones [26].

And the smoke of the fatherland is sweet and pleasant to us...The popularization of smoking began about a hundred years ago, since then the number of smokers has been growing relentlessly.

Today there are about a billion smokers on Earth. Nevertheless, in recent decades there has been a trend towards a decrease in the proportion of smokers in the population. So, in 1980, 40% of men and 10% of women in the world smoked daily, in 2012 these numbers decreased to 30% and 6%, respectively.

The popularity of smoking is falling globally, but unfortunately not in Russia, where 38 million people smoke on average more than 20 cigarettes a day, as 40 years ago. Russia today ranks second in the world in tobacco consumption after China [27].

It remains to be hoped that the development of tobacco legislation in Russia will mitigate these harsh statistics, but at the same time it must be remembered that responsibility for our health lies primarily with ourselves, and not with the state.

I wish you good health,
Your author is a former smoker with five years of experience.
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