C 025: GENETIC VARIATION IN SMOKING AND LUNG CANCER

Excerpt:


J Pharm Pharmacogn Res 2(Suppl. 1): S70, 2014 Special supplement with the abstract book of LATINFARMA 2013 Conference C 025: GENETIC VARIATION IN SMOKING AND LUNG CANCER Tyndale R. Centre for Addiction and Mental Health, Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, Canada. Abstract Nicotine is the main active component in cigarette … Continue reading C 025: GENETIC VARIATION IN SMOKING AND LUNG CANCER

J Pharm Pharmacogn Res 2(Suppl. 1): S70, 2014

Special supplement with the abstract book of LATINFARMA 2013

Conference

C 025: GENETIC VARIATION IN SMOKING AND LUNG CANCER

Tyndale R.

Centre for Addiction and Mental Health, Departments of Psychiatry, Pharmacology and Toxicology, University of Toronto, Toronto, Canada.
Abstract

Nicotine is the main active component in cigarette which mediates tobacco dependence. About 80% of nicotine is metabolically inactivated to cotinine; the hepatic CYP2A6 enzyme is responsible for over 90% of this conversion. Both in vivo and in vitro studies demonstrate considerable interindividual variation in CYP2A6 activity that is attributed to variations in the CYP2A6 gene. Individuals with at least 1 copy of the genetically inactive or reduced activity CYP2A6 variant (allele) have decreased nicotine metabolism.

We have found that slow nicotine inactivators are ≈2 times less likely to be dependent smokers (OR 0.52 95% CI 0.29-0.95). Slow metabolizers that do become smokers consume 7-10 cigarettes less per day than normal metabolizers, and also inhale less deeply. There are large differences among ethnic populations in the frequency of slow metabolizers which may contribute to the ethnic differences observed in rates of smoking and tobacco-related diseases. In general the frequencies of variant alleles with large impacts on function are low in Caucasians, while some of the alleles are prevalent (up to 20%) for example in Asian and African populations. Variation in CYP2A6 genotype and/or the CYP2A6 metabolite ratio biomarker is associated with differences in the ability to quit smoking both in the absence of pharmacotherapy, and with nicotine replacement therapies. We found the odds of quitting with nicotine patch were reduced by 30% with each increasing quartile of the ratio; faster metabolizers were less successful in quitting than slow metabolizers.

CYP2A6 is also capable of activating tobacco-procarcinogens such as NNK. Thus individuals with slower CYP2A6 smoke less and activate less tobacco-smoke procarcinogens resulting in lowered risk for tobacco- and dietary-related cancers such as lung cancers, while those with high levels of CYP2A6 are at greater risk. We have also shown that having a variant in the α3-α5-β4 nicotinic receptor cluster, a target for both nicotine and nitrosamines, also alters smoking and lung cancer risk. When examining variation in CYP2A6 and the nicotinic receptor variant together we observe an increase in both smoking and lung cancer risk for those who are faster CYP2A6 metabolizers and have the at risk nicotinic receptor variant.

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