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A natural advantage against the cigarette

Almost 40% of Brazilian possess mutations that favor smoking less

Four out of every ten Brazilians carry with them a gene alteration, named CYP2A6, which can represent a biological advantage in the fight against smoking. People with this gene mutation, which acts in the process of elimination (metabolizing) of the nicotine liberated by the tobacco into the blood and brain of smokers, tend not to smoke or are less addicted to the cigarette than individuals with a normal version (which is predominant) of the CYP2A6. This is good news from a study carried out by researchers from the National Cancer Institute (Inca), of Rio de Janeiro, which mapped out the occurrence of the four principal CYP2A6 mutations within a sample of 342 individuals, composed of smokers, former smokers and individuals who have never smoked.

The work produced an important piece of information, especially for a country so well racially mixed as Brazil: the most common of these mutations that reduce chemical dependence on the cigarette is called 1B, and is a lot less frequent in people African origin or in mulattos than in whites. “This data is very interesting and unprecedented in scientific literature”, comments the medical doctor Guilherme Kurtz, from Inca, the study’s coordinator. “International studies on the incidence of mutations of this gene had been done only with Caucasian and Asiatic populations.”

Without taking their ethnicity into account, 31% of the individuals who participated in the Inca study presented at least one copy (allele) of the gene CYP2A6 as the mutation 1B, an index within the international average found in countries with populations formed in the majority by descendants of Caucasians. As is known, the human being possesses two copies of his/her genes, one inherited from the father and the other from the mother – and each one of them may or may not be the target of mutations.

The results of the work indicate that the presence of this genetic alteration is seven times greater in non-smokers and twice as high in ex-smokers than in habitual smokers. When skin color was adopted as a differential of the research’s participants, the occurrence of the principal mutation in CYP2A6 varied considerably. At least one altered allele is present in 38% of whites, 30% of mixed color and in only 15% of blacks. “It is interesting to observe how the frequency of mutation varies in accordance with the classification of the individuals according to skin color”, says the biologist Gisele Vasconcelos, from Inca, another of the study’s authors. The analyzed sample was composed of 147 white individuals, 141 mulattos and 54 blacks, a spread, in a rough manner, of the racial standard distribution within the country. The number of men and women was more or less the same – and the sex parameter appears not to be relevant in the incidence of these genetic alterations.

As well as the not very rare 1B mutation, the incidence of three other types of alteration in the CYP2A6 gene was determined at the Inca laboratories. The second most frequent of them is called “9”, found in 6% of the study’s participants. After appears mutation “2”, present in 2% of the sample’s individuals. And finally, in last place comes “4”, with an incidence of 0.6% of the Brazilians analyzed (in Japan this mutation comes about in every five of its inhabitants). Summing up the prevalence of the four mutations (1B, 9, 2 and 4), 39% of the national population possess forms of the CYP2A6 gene that could diminish the risk of dependency on nicotine – therefore of smoking – and increases the chances of stopping smoking.

Why do these mutations appear to push away people from the cigarette? In June of 1998, researchers at the University of Toronto, in Canada, demonstrated that the action of the gene is an important element in the chemical chain that holds the smokers to tobacco. The gene commands the production in the liver of a hormonal enzyme, also called CYP2A6, which, among other functions, plays the role of regulating the destruction of nicotine, present in the bloodstream and in the smoker’s brain. The more that the nicotine is eliminated by the action of the enzyme the greater does the smoker feel the need to light up another cigarette in order to replace the levels of this substance. Some scientists believe that, once the chemical dependency in relation to nicotine has been established, the smoker always looks to maintain high levels of this substance in his/her organism. Hence the compulsion to consume tobacco.

Reduced activity
In this context, individuals who show some alteration in the CYP2A6 gene, such as the mutations cited (along with a further nine, rarer and not mentioned), manufacture different non-conventional forms of the enzyme. People with the mutations 1B and “9”, the most prevalent in the Brazilian population, for example produce variants of this enzyme that are less active. And it is as if they naturally carry a smaller quantity of the enzyme in their organism, and for this reason the process of destruction of nicotine is at a slower rate.

As the levels of nicotine in the blood and brain take longer to decline, the carriers of these genetic modifications, if they were to smoke, would manage to satisfy their vice with only one or two cigarettes. However, individuals with mutation “2” produce an inactive form of the enzyme and those with alteration “4” simply don’t produce it. In practical terms this is equivalent to saying that the persons with these mutations practically do not produce the enzyme in question – or at least it is not produced by the action of the CYP2A6 gene. It could well be that some other gene produces some quantity of this enzyme, but not with the same efficiency of the original gene, the CYP2A6. Abroad, medicines are being tested that are capable of imitating the effect of the mutations and inhibiting or at least retarding the action of the enzyme, which could well be an important step to diminish the dependency in relation to nicotine.

Double benefit
Besides making the destruction of nicotine slower, and thus diminishing the desire to smoke, the mutations give a second type of gain to their carriers: they reduce the level of activation of pre-cancerigenic substances present in the tobacco derivatives. This is because, in the organism, the normal form of the CYP2A6 activates the nitrosamines, toxic substances found in the cigarette, and transforms them into elements that are predisposed towards cancer. However, in the abnormal versions of the enzyme, coming from genetic modifications, this does not happen. “The mutations are doubly beneficial”, comments Gisele.

Logically, the genetic situation is not the only factor that could favor or inhibit smoking. Cultural and socioeconomic aspects also play a part. Within the richest nations the consumption of cigarettes has fallen for decades. The same thing has not occurred in the poorer regions. So much so that 80% of the 1.3 billion smokers in the world are from developing countries. In Brazil, where around 200,000 people die per year as a result of health problems related to smoking, such as heart attacks, emphysema, strokes and cancer, the consumption of cigarettes per capita fell by 32% between 1989 and 2002. But there are twice as many smokers at the lowest educated levels – probably the poorest as well – than in the wealthier sectors of the population.