The cytochrome P450 (CYP) family is the principal enzyme system involved in the metabolism of xenobiotics and endogenous compounds. Among this family, CYP2A6 is one of the most important enzymes for metabolism of nicotine. In this study, the linkage of CYP2A6*1 and CYP2A6*4 genotypes with nicotine metabolism was investigated. A single polymerase chain reaction–restriction fragment length polymorphism was used to resolve the genotypes into CYP2A6*1 (wild type), CYP2A6*2, or CYP2A6*3. The population studied consisted of 200 healthy smokers from Mashhad city, North East of Iran. The urinary cotinine as the principal metabolite of nicotine was analyzed for 12 subjects (7 subjects with CYP2A6*1 as controls and 5 subjects with CYP2A6*4). The results indicated that cumulative urinary cotinine excretion in CYP2A6*4 genotype was about one-eighth compared with the control group (wild type). Cotinine formation from nicotine has individual and ethnic variability that correlated with the level of CYP2A6 expression. Moreover, urinary cotinine level was drastically lower in CYP2A6*4 subjects than in CYP2A6*1 subjects.
Get full access to this article
View all access options for this article.
References
1.
AoyamaT., YamanoS., GuzelianP.S., GelboinH.V., GonzalezF.J.1990. Five of 12 forms of vaccinia virus-expressed human hepatic cytochrome P450 metabolically activate aflatoxin B1. Proc Natl Acad Sci USA, 87:4790–4793.
2.
BehravanJ., NaghibiM., MazloomiM.A., HassanyM.2006. Polymorphism of angiotensin II type 1 receptor gene in essential hypertension in Iranian population. Daru, 14:82–86.
3.
ChenG.F., TangY.M., GreenB., LinD.X., GuengerichF.P., DalyA.K., CaporasoN.E., KadlubarF.F.1999. Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method. Pharmacogenetics, 9:327–332.
4.
CrespiC.L., PenmanB.W., GelboinH.V., GonzalezF.J.1991. A tobacco smoke-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, is activated by multiple human cytochrome P450s including the polymorphic human cytochrome P4502D6. Carcinogenesis, 12:1197–1201.
5.
DempseyD., TutkaP., JacobP., AllenF., SchoedelK., TyndaleR.F.2004. Nicotine metabolism ratio as an index of cytochrome P450 2A6 metabolic activity. Clin Pharmacol Ther, 76:64–72.
6.
EmamghoreishiM., BokaeeH.R., KeshavarzM., GhaderiA., TyndaleR.F.2008. CYP2A6 allele frequencies in an Iranian population. Arch Iran Med, 11:613–617.
7.
Fernandez-SalgueroP., HoffmanS.M.G., CholertonS., MohreweiserH., RaunioH., RautioA., PelkonenO., HuangJ.D., EvansW.E., IdleJ.R., GonzalezF.J.1995. A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles. Am J Hum Genet, 57:651–660.
8.
FukamiT., NakajimaM., HigashiE., YamanakaH., McLeodH.L., YokoiT.2005. A novel CYP2A6*20 allele found in African- American population produces a truncated protein lacking enzymatic activity. Biochem Pharmacol, 70:801–808.
9.
GullstenH., AgúndezJ.A., BenitezJ., LaaraE., LaderoJ.M., Diaz-RubioM., Fernandez-SalgueroP., GonzalezF., RautioA., PelkonenO., RaunioH.1997. CYP2A6 gene polymorphism and risk of liver cancer and cirrhosis. Pharmacogenetics, 7:247–250.
10.
HukkanenJ., JacobP., BenowitzN.L.2005. Metabolism and disposition kinetic of nicotine. Pharmacol Rev, 57:79–115.
11.
KitagawaK., KunugitaN., KatohT.1999. The significance of homozygous CYP2A6 deletion on nicotine metabolism: a new genotyping method of CYP2A6 using a single PCR-RFLP. Biochem Biophys Res Commun, 262:146–151.
12.
KokabaN.A., CholertonS., KarakayalA.E.2001. Determination of coumarin metabolism in Turkish population. Hum Exp Toxicol, 20:179–184.
13.
LahiriD.K., NurnbergerJ.I.1991. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res, 19:5444.
14.
MillerJ.A., AnactaL.A., CattranD.C.1999. Impact of gender on the renal response to angiotensin II. Kidney Int, 55:278–285.
15.
NakajimaM., YamamotoT., NunoyaK., YokoiT., NagashimaK., FunaeY., ShimadaN., KamatakiT., KuroiwaY.1996a. Characterization of CYP2A6 involved in 3'-hydroxylation of cotinine in human liver microsomes. J Pharmacol Exp Ther, 277:1010–1015.
16.
NakajimaM., YamamotoT., NunoyaK., YokoiT., NagashimaK., InoueK., FunaeY., ShimadaN., KamatakiT., KuroiwaY.1996b. Role of human cytochrome P4502A6 in C-oxidation of nicotine. Drug Metab Dispos, 24:1212–1217.
17.
NakajimaM., YokoiT.2005. Interindividual variability in niocotine metabolism: C-oxidation and glucoronidation. Drug Metab Pharmacokinet, 20:227–235.
18.
OscarsonM., GullstenH., RautioA., BernalM.L., SinuesB., DahlM.L., StengårdJ.H., PelkonenO., RaunioH., Ingelman-SundbergM.1998. Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett, 438:201–205.
SchoedelK.A., HoffmannE.B., RaoY., SellersE.M., TyndaleR.F.2004. Ethnic variation in CYP2A6 and association of genetically slow nicotine metabolism and smoking in adult Caucasians. Pharmacogenetics, 14:615–626.
21.
TakedaN., JitsunariF., AsakawaF., SunaS., ManabeY., FukanagaI., GotohA.1993. Simultaneous determination of cotinine and creatinine by high performance liquid chromatography. Jpn J Ind Health, 35:198–199.
22.
XuC., GoodzS., SellersE.M., TyndaleR.F.2002. CYP2A6 genetic variation and potential consequences. Adv Drug Deliv Rev, 54:1245–1256.
23.
YamanakaH., NakajimaM., NishimuraK., YoshidaR., FukamiT., KatohM.2004. Metabolic profile of nicotine in subjects whose CYP2A6 gene is deleted. Eur J Pharm Sci, 22:419–425.
24.
YamazakiH., InoueK., HashimotoM., ShimadaT.1999. Roles of CYP2A6 and CYP2B6 in nicotine C-oxidation by human liver microsomes. Arch Toxicol, 73:65–70.
25.
YangM., KunugitaN., KitagawaK., KangS.H.2001. Individual differences in urinary cotinine level in Japanese smokers: relation to genetic polymorphism of drug-metabolizing enzymes. Cancer Epidemiol Biomarkers Prev, 10:589–593.
26.
ZabetianC.P., GelernterJ., CubellsJ.F.2000. Functional variants at CYP2A6: new genotyping methods, population genetics, and relevance to studies of tobacco dependence. Am J Med Genet, 96:638–645.
