Genetically determined metabolism of nicotine and its clinical significance

Abstract

Enzymes of the cytochrome P-450 (P450) which belong to the family of oxidase enzymes, are present in cells of all organisms and play a major role in the first phase of xenobiotic metabolism. There are several isoenzymes of P450 and associated with them differences in the speed of metabolism: poor-, extensive- and ultrarapid. Nicotine undergoes biotransformation in the liver mainly by CYP2A6 isoform of CYP 450. There are many polymorphic forms of CYP2A6 affecting the metabolism of nicotine. There are also several CYP2A6 activity inhibitors and inducers among commonly used drugs. Ability of CYP2A6 isozymes to activate certain procancerogenic substances present in cigarette smoke makes their polymorphism more significant. Moreover, some isoforms may have also influence on the risk of lung cancer development by affecting the enzymatic activation of tobacco-specific nitrosamines. Metabolism of nicotine, mainly through CYP2A6, has also many clinical implications, from one side connected with the efficacy and safety of the nicotine replacement therapy, on the other hand related to the occurrence and route of several diseases. This makes the type of nicotine metabolism a potential predictor of the clinical outcomes in patients with cardiovascular disease, addicted to nicotine and those using nicotine replacement therapy, as well as ones taking other medications.The purpose of this work is to summarize the current knowledge about the variation in genetically determined metabolism of nicotine and its clinical significance.