Future Implications of the

2'-Hydroxylation Pathway:

Scientific and Societal Implications

 

 

Smokers and Increased Health Risks -- In a separate review publication, Hecht (1999) cites the certainty that NNK is most definitely present in cigarette smoke and that it has direct effects on humans and lab animals. The evaluation states that the presence of NNK in cigarette smoke, as well as the pulmonary carcinogenicity of NNK in rodents, and the evidence for human uptake of NNK while smoking have all been demonstrated with "clear evidence" and "strong reproducible results." Carcinogenic precursors are found in mainstream smoke inhaled by a smoker as well as sidestream smoke from cigarettes regardless of whether or not a filter is present. Although each dose of carcinogen from a cigarette is a very small one, years of smoking will indubitably produce substantial damage to a variety of body tissues and processes (Hecht 1999).

Nicotine and Society: Further Education Required -- Evidence that NNK poses a substantial threat to smokers as well as ex-smokers on nicotine replacement therapy is a cause for major concern. The data presented here indicates that much is already known about nicotine metabolism and the effects of nicotine metabolites on human tissues. Although research will continue to probe the consequences of smoking and the metabolism involved in the breakdown of compounds present in cigarettes, the scientific information already published regarding these topics must be broadcast to the general public. The conclusions drawn from the research summarized above provide yet another reason for people to quit smoking or to never begin in the first place. Evidence such as this must be presented via the popular media to strengthen anti-smoking programs and campaigns. Furthermore, nicotine replacement therapy has a previously unknown inherent danger in the activation of nicotine metabolites. It is quite likely that most people undergoing nicotine replacement are unaware of this, but a mandatory a warning label on nicotine replacement products such as nicotine gum and the nicotine patch would eliminate such ignorance. If people trying to quit smoking understood that ingesting nicotine puts them at a higher risk for the development of lung cancer, they would perhaps be less likely to prolong their course of replacement therapy.

Possibility for Gene Therapy? -- The evidence linking the activity of cytochrome P450 2A6 with the genetic CYP2A6 alleles suggests a possibility for future gene therapy for smokers who want to cease smoking. The small percentage of people with inactive CYP2A6 alleles in the population are much less likely to become addicted to nicotine or to develop tumors derived from nicotine metabolites (Oscarson 1999). Although most methods of gene therapy are not currently practiced, the fast pace at which genomic technologies are advancing makes gene therapy a possible future realization. Nicotine metabolism is yet another component that could be manipulated by gene therapy-altering the CYP2A6 locus to inactivate both alleles would prevent the patient from becoming nicotine-dependent and greatly decrease the chances of carcinogenesis from NNK and NNAL. However, a possible negative outcome of this scenario is that a patient who had received such gene therapy would continue to smoke with the knowledge that he/she was at a reduced risk for cancer, disregarding the vast multitude of other health problems caused by smoking.

Future Research -- A virtual plethora of scientific literature exists documenting the pathways and effects of nicotine metabolism. Much is already known about nicotine metabolite structures, pathways, and influences on body tissues. Certainly, this field of research will continue to explore the consequences of tobacco products on the human body, and the metabolic pathways that govern these effects. Areas of future interest include further investigation into the 2'-Hydroxylation pathway, as this is a relatively novel undertaking. Additionally, while much data exists for the effects of carcinogenic metabolites on the tissues of rodents, less is known about the results of these same metabolites when human and other primate tissues are treated with NNK and NNAL. For example, human lung tissue displays a much less active alpha-hydroxylation pathway of NNK than rodent and monkey tissues (Hecht et al 1999). The data presented for rats, mice, and hamsters is likely indicative of nicotine metabolite activation in humans, but more research with human tissues may be necessary to understand exactly how similar these mechanisms are.

 

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