ICANCERRESEARCH56.251-253.ianuaiy 15.19961 Advances in Brief

The Effect of Tobacco on Lung Cancer Risk Depends on CYP2D6 Activity'

Christine Bouchardy,2 Simone Benhamou, and Pierre Dayer

Geneva Cancer Registry. Boulevard de Ia Cluse 55, 1205 Geneva, Switzerland (C. B.J; Unit of Cancer Epidemiology (INSERM U351), Gustave Roussy Institute. 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France (S. B.J; and Division of Clinical Pharmacology, University Hospital of Geneva, 24 rue Micheli-du-Crest. 1211 Geneva, Switzerland (P. D.J

Abstract observed in cases. Genetically determined oxidative CYP2D6 activity was scored through the use of the probe drug dextromethorphan, a nonprescription The geneticallydeterminedP450CYP2D6 activityis suspectedtobe coughsuppressant.Patientswererecruitedby oneof the seventrainedstudy involved in lung carcinogenesisby activating carcinogenscontained in interviewers who determined eligibility through a short questionnaire. Each tobaccosmoke.Therefore,lungcancerriskshoulddependonbothsmok interviewerhad to include both casesand controls.All casesand controls ing exposureand CYP2D6activity. The extentto which CYP2D6activity, includedin the study were smokers,definedas peoplehaving smokedfive determinedby usingdextromethorphan,couldmodifythe effectof to cigarettesor more(or cigarsor pipes)per day during at least5 years.Each baccowasevaluatedfrom a study on 128lung cancersand 157controls. subject was screenedaccordingto the main following exclusion criteria: A stronginteractionwasobserved;theeffectof tobaccoonlungcancer refusalto give informed consent,use of generalanesthesiawithin the last risk rosewith IncreasingCYP2D6activity (P < 0.001).Increasinglevelsof 5 days,presenceof severerenal diseaseor severeliver disease,or severe smoking increased lung cancer risk only among smokers with the highest chronicheartfailureor medicationduringthelastweekwith anydrugsknown CYP2D6 activity, and CYP2D6 was a risk factor only among heavy or suspectedtointerferewith the test.3Data were collectedon sociodemo smokers.Smokers with both the highest CYP2D6 activity and daily to graphic and anthropomorphic characteristics, recent and former tobacco use, baccoconsumptionwereat very highrisk for lungcancer.Theseresulis and occupationalhistory. Women representedlessthan 7% of the study may explain discrepantresulisof previousstudieson the association population, and the analysis was performed only among males, i.e., 128 lung betweenCYP2D6 activIty and lung cancer. cancersand157controls. Beforegoing to bed,subjectswererequestedtoempty their bladderand Introduction weregiven 25 mg of dextromethorphanhydrobromide.An 8—12-hovernight Procarcinogens contained in tobacco smoke must be activated in urinespecimenwascollected,anda urinesamplewasfrozen(at —20°C)and analyzedwithin 3 months.All phenotypinganalyseswereperformedblind in the organism before becoming ultimate carcinogens (1). The geneti the Division of Clinical Phannacologyinthe UniversityHospitalof Geneva, cally determined oxidative capacity of the cytochrome P450 CYP2D6 Switzerland.Interindividualdifferencesin ratesof dextromethorphanoxida is suspected to be involved in this activation (2). Since 1984, the lion to its O-demethylatedmetabolite,dextrorphan,wereexpressedastheMR4 relationship between lung cancer risk and the CYP2D6 phenotype of urinary dextromethorphantodextrorphanandwere determinedby high and/or genotype has been the subject of numerous studies, and the performance liquid chromatography/fluorescence (5). association still remains controversial (3). If this cytochrome really Unconditional multivariate logistic regression was used to estimate the RRs affects smoking-induced lung cancer by activating tobacco procar of lung cancerand the 95% confidenceintervals(6). All modelswere log cinogens, then the effect of smoking on lung cancer risk should linear,fitted usingthegeneralizedlinearinteractivemodelingstatisticalpack increase with the level of CYP2D6 activity. The highest effect should, age(7).Accordingto theaimof thestudy,whichwasto analyzetheinteraction therefore, be found among individuals having the highest levels of betweenCYP2D6 activity and levels of smoking, CYP2D6 activity was studiedbothasa continuousvariable(thelogarithmof theMR), asa categor both smoking and CYP2D6 activity. Thus far, no assessment was ical one in three levels according to the tertile of the control distribution (log made of the role that this genetic predisposition to carcinogen acti @ MR —1.8, —2.5 log MR < —1.8, log MR < —2.5) and as the vation plays, according to the extent of tobacco exposure. The aim of conventionalclassificationof phenotype“extensive―(MR0.3) versus the present case-control study was not to reassess the well known “poor―(MR> 0.3) metabolizers.The daily consumptionof eachtype of effect of tobacco exposure or the possible effect of the CYP2D6 tobaccowasexpresseding/day(1 g for cigarette,2g for cigar,and3 g for activity but to evaluate among smokers the extent to which CYP2D6 pipe) and was calculatedby dividing the cumulativelifetime tobaccocon activity could modify the effect of tobaccoon lung cancer risk to sumption by the overall duration of smoking. The interaction between identify smokers at very high risk. CYP2D6activity andaveragedailyconsumptionoftobaccowasstudiedtotest theequalityof the RRsacrossthethreelevelsof smokingwithin eachof the Patients and Methods threeoxidative levels (heterogeneitytest)and to evaluatea potentiallinear variationof smokingeffect with increasinglevelof CYP2D6activity (trend A case-controlstudywasperformedin Francefrom 1988to 1992.All case test;Ref.6). All modelswereadjustedforthemaineffectsof thestudiedrisk andcontrolindividualsweresmokers,recruitedin 10hospitals.Caseswereall factorsandotherrisk factorsfor lungcancerrelatedto tobaccoorprofessional eligible Caucasianpatientswith histologicallyconfirmedsquamousorsmall exposureandfor age.Sevenbinary variableswerecreatedaccordingto the cell primary lung cancers.Adenocarcinomaswerenot includedin the study different typesof medication(sedatives,antihypertensiveanddiuretic drugs, because they were less strongly associated with tobacco (4). Control individ cardiotonics, anti-infectious drugs, analgesics, vitamin and trace elements, and ualswereall eligible Caucasianpatientswithoutpreviousor actualmalignant otherdrugs)andweretakeninto accountin all analyses. disease and were recruited according to age, sex, and hospital distributions Results Received 9/21/95; accepted I 1/29/95. The costsof publicationof this article were defrayedin part by the paymentof page Of the 128 lung cancercasesin males, 81 (63%) were squamous charges.Thisarticle mustthereforebeherebymarkedadvertisementinaccordancewith and 47 (37%) were small cell carcinomas. The main diagnoses of the 18 U.S.C. Section 1734 solely to indicate this fact. I This work was supported by the Swiss Cancer League, Switzerland (F0R063); The League against Cancer of Fribourg, Switzerland (F0R063); Cancer Research,Switzerland 3 Neuroleptics, antidepressants, antiarrythmics, a-blockers, and drugs containing ci (AKT 617); and Fund for Clinical ResearchagainstCancer, Gustave RoussyInstitute, metidine, debrisoquine, dextromethorphan, dextropropoxyphene, diltiazem, guanoxan. Villejuif, France(88D28). phenacetine, phenformine, or phenotiazine. 2 To whom requests for reprints should be addressed. Phone: (41 22) 329 10 1 1; Fax: 4 The abbreviations used are: MR. metabolic concentration ratio; RR, relative risk; CI, (41 22) 328 29 33. confidence interval. 251

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157 controls were rheumatological diseases(32%), infectious and pam with highest CYP2D6 activity, smokers of at least 30 g of tobacco/day sitic diseases(12%), cardiovasculardiseases(10%), and respiratory dis had a 5-fold increased risk compared with smokers of 20 g or less. eases (10%). The mean age was slightly greater (P < 0.05) among the When the continuous variables were used rather than the categorical lung cancer patients (mean, 58.0; SD, 9.4) than among the controls variables, similar results were obtained. Conventional classification of (mean,54.3; SD, 10.3).All individuals were smokers,and about 75% of phenotype “extensive―versus“poor―metabolizersalso provided sim casesand of controls were smokers of cigarettesexclusively; the 25% ilar findings (f for interaction = 3.7; P = 0.054). The constraint of remaining were almost entirely smokers of cigarettes associatedwith this two-group classification implies very few poor metabolizers (10 anothertobaccoproduct. According to our recruitment criteria, chosento casesand 12 controls), leading to low statistical power, and it was not have only regular smokers, the variability between cases and controls possible to study the effect of CYP2D6 phenotype with more than two concerning tobacco exposurewas small, and the only significant differ classes of tobacco. The risk associated with “extensive―phenotype ence between cases and controls in tobacco exposure was the mean compared to “poor―oneswas 0.42 (95% CI, 0.10—1.71)among duration of smoking, which was greater (P < 0.001) among cancer smokers of 20 g/day or less and increased to 3.15 (95% CI, 0.60— patients (mean, 37.6; SD, 9.7) than among controls (mean, 31.7; SD, 16.50) among smokers of more than 20 g/day. 10.6).Approximately 14%ofcases and 5% ofcontrols reporteda history No significant interaction between CYP2D6 activity and duration of occupational exposureto asbestosor arsenic.The frequency distribu of smoking (or with measuresof other tobacco or occupational expo tion of the log MR showed a bimodal distribution with values ranging sure) was found. The results were not affected by adjustment on the from —4.0to0.7, and with a gap between —0.2and—0.6. seven variables of medication intake; therefore, the RRs were pre After adjusting for age and for all variables related to tobacco and sented without such adjustment. occupational exposuresas confounding factors, there was no effect of CYP2D6 activity on lung cancer risks. The adjusted estimates of the RRs Discussion of lung cancer among smokers with medium or high CYP2D6 activity were 1.02 (95% CI, 0.53—I.96)and 0.82 (95% CI, 0.43—1.56),respec This study found significant interaction between daily consumption tively, compared with smokers with low activity. Results were quite of tobacco and CYP2D6 activity and shows, for the first time, that similar when considering separatelysquamousor small cell carcinomas. increasing levels of smoking increased the risk of lung cancer only A strongsignificantpositive interactiveeffect on the risk of lung among one-third of smokers with the highest level of CYP2D6 activ cancer was observed between the CYP2D6 activity and the average ity. The highest risk for this cancer (RR, 4.95; 95% CI, 1.61—15.23) daily consumption of tobacco. The effect of tobacco consumption was was observed among smokers having the highest levels of both significantly different according to the individual CYP2D6 activity, tobacco consumption and CYP2D6 activity. As the study concerns and vice versa (f for homogeneity = 13.9, for 4 degreesof freedom; only smokers, all the reported risks would have to be greater if P = 0.005). This interaction showed a significant positive trend account was taken for the basal difference of lung cancer risk between (x2 10.5,foronedegreeoffreedom,P< 0.001)withincreasingsmokers and nonsmokers. The absenceof tobacco effect in smokers effect of daily tobacco consumption related to increased CYP2D6 with low CYP2D6 enzyme activity does not mean that smoking per se activity or equivalently an increasing effect of CYP2D6 activity with has no effect among them. Similarly, CYP2D6 activity was a risk increasing levels of smoking. factor of lung cancer only among heavy smokers (>30 g/day), with a RRs of lung cancer according to daily consumption were estimated 3.53-fold increased risk (95% CI, 1.06—11.77) among those having for each level of CYP2D6 activity, and the results are summarized in the highest CYP2D6 activity compared to those having the lowest Table 1. Within both the low and the medium classes of CYP2D6 CYP2D6 activity. Among lighter smokers, no relation was found activity, RRs of lung cancer were not significantly different accross between CYP2D6 activity and lung cancer risk. the three levels of tobacco consumption, and no dose-response effect Theseresultsarelikely not explainedby differencesbetweencasesand of tobacco was observed. In contrast, the corresponding RR estimates controls in age, professional exposure,duration of smoking, or medica at the high level of CYP2D6 activity were significantly different tion use,becausetheseconfounderswere taken into accountin analyses. (P < 0.02), with a strong dose-response effect of risk with an Similar results were obtained when also adjusted for use of tobacco increasing level of tobacco smoked (P < 0.006); among individuals product other thancigarettes.The resultsdid not differ betweencentersof recruitment and were not modified when the analyseswere performed both in malesandfemales.It is unlikely that our resultsreflect a selection Table 1 Number of cases/controls and estimates of adjusted RRs―(95%CI) of lung cancer according to average daily consumption of tobacco by level of bias in the control group becauseno associationwas found within this CYP2D6activityLevel control group between CYP2D6 activity and either the main medical activityLow of CYP2D6 diagnoses,hospitals, or interviewers. These findings are consistent with the hypothesis that CYP2D6 is HighDaily Medium involved in smoking-induced lung cancer by activating tobacco car consumption of log MR —2.5 log MR log MR cinogens. The fact that increasing levels of tobacco consumption have —2.5@2Otobacco(g/day) —1.8 < —1.8 < no effect on lung cancer risk among individuals with a low CYP2D6 1.0 1.0 1.0 15/3021—30 26/17 17120 activity underlines the importance of carcinogen activation by CYP2D6.Crespietal. (2)demonstratedthatanimportantcarcinogen 0.43 (0.14—1.37) 1.04 (0.30—3.60) 1.43 (0.42—4.85) 9/13>30 8/16 12/10 in tobacco, 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone, is acti 0.40 (0. 13—1.15) 0.43 (0. 14—1.34) 4.95 ( I .61—15.23) vated by CYP2D6 enzyme, and low CYP2D6 oxidators have little or 17/10Homogeneity 12/18 10/20 no capacity to activate this carcinogen by this metabolic way. Re <0.02Trend test (P) NS6 NS cently, CYP2D6 was also suggested to be involved in nicotine me <0.006atest (P) NS NS tabolism (8). The interaction reported here was not present when

Adjusted for age (<50, 50—54, 55—59, 60—64, 65), duration of smoking tobacco exposure was measured either as the duration of smoking or (<25, 25—29,30—34,35—39,and 40), smoking status (exsmokers and current smokers), the ageat beginning of smoking, instead of daily amount. A biological inhalation (no/yes), age at smoking initiation (> 18, 17—18,and 16), asbestosexposure reasonable hypothesis, therefore, is that the genetically ability to (no/yes),andarsenicexposure(no/yes). b NS, not significant. activate procarcinogens via CYP2D6 is manifested only in responseto 252

Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1996 American Association for Cancer Research. CYP2D6 ACTIVITY. TOBACCO. AND LUNG CANCER RISK a high averagedaily exposure. Activation of 4-(methylnitrosamino)-l- those at very high risk of lung cancer. This risk could then be reduced (3-pyridyl)-l-butanone to cytotoxic and mutagenic speciesis associated for people having both high CYP2D6 activity and tobacco exposure with more than one cytochrome P450 form (2). The specific CYP2D6 is and being unable to stop smoking by blocking this metabolic way. not likely to be the only P450carcinogenactivator. Recently,two studies Acknowledgments (9, 10) demonstratedthat lung cancer susceptibility associatedwith the CYP1AI and CYP2E1 polymorphism (other P450sidentified asplaying WewouldliketothankProf.N. Breslow,Dr.C.Bonaiti-Pellié,andDr.P.Ward a role in lung carcinogenesis)differed greatly according to the level of for theirhelpfulcommentsonthemanuscript;Prof.P.Albertofor hisencourage smoking; thosecytochromeswere ascribedto a remarkablerisk elevation mentto initiatethestudy;R. StriberniandProf.M. M. Galteaufortheirexpert only at the lower cigarette dose level. Together, these results strongly technical help; C. Paoletti and M. Labbéfortechnical assistance;andT. Pamm for editorialassistance.Wearealsoindebtedtotheconsultantsandchiefsof Clinical suggest that the activity of these cytochromes is closely associated with units who gave us the opportunity to study their patients for the purpose of the lung cancer risk among populations with low smoking exposures.In study:Drs G. Akoun,R. Arriagada,P.Baldeyrou,F.Besancon,A.Bisson,M. contrast, the deficient activity of the glutathione S-transferaseMl, an Bisson, F. Blanchet, F. Blanchon, A. Bouchiki, J. Brugere, C. Buffet, J. P. Camus, isoenzyme involved in some tobacco carcinogens detoxification, in R. Caquet,Y.Chapuis,D.Chassagne,P.Constans,B.Dautzenberg,J.Debray, creasedlung cancer risk mostly in the heaviestsmokers (11). CYP2D6 J.P. Derenne,P.Duroux,J.Fain,G. Freyss,A.Gerbaulet,P.Girard,J.Guerre, may also play a major role in the carcinogenesisof lung cancer in P. Guibout,H.Hamard,B.Housset,J.C. Imbert,F. Janot,A. Jardin,T. Le populations with high smoking exposure. Chevalier, B. Lebeau, A. M. Leridant, P. Levasseur, V. G. Levy, A. Livartowski, It is possible that tobacco induces a P450 isoform that is also G. Loyau, B. Luboinski, 0. Mamelle, F. Mazas, P. Marandas, C. Menkes, involved in dextromethorphan metabolism. However, some data sup H. Mondon, J. P. Passeron, J. Piquet, M. Robillard, J. Rochemaure, R. Roy port the view that smoking does not modify CYP2D6 phenotype (12), Camille,J. C. Saltiel,G. Schwaab,J.M. Segrestaa,D.Sereni,M. Spielmann, P.Testas,0.Tobelem,andP.Vige. but our results should, nevertheless, be confirmed. Another possible explanation to the present results would be the coinheritance of References closely linked genes on the same chromosome, so that deficient 1. Gonzalez, F. J., and Idle, J. R. Pharmacogeneticphenotypingandgenotyping:present CYP2D6 polymorphism servesjust as an indicator for unknown genes status and future potential. Clin. Pharmacokinet., 26: 59—70,1994. involved in cancer susceptibility. 2. Crespi C. L, Penman,B. W., Gelboin, H. V., and Gonzalez,F. J. A tobacco smoked-derived nitrosamine, 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone, is ac The importance of CYP2D6 activity as a risk factor for lung cancer tivated by multiple human cytochrome P450s including the polymorphic human is seen only after stratification both on CYP2D6 activity and tobacco cytochromeP4502D6. Carcinogenesis(Lond.), 12: 1197—1201,1991. consumption. This may explain the apparent lack of coherenceamong 3. Caporaso, N., DeBaun, M. R., and Rothman, N. Lung cancer and CYP2D6 (the débrisoquinepolymorphism) sources of heterogeneity in proposed association. Phar the findings of previous studies, which have not considered that the macogenetics,5: 129—134,1995. level of smoking can modify the effect of CYP2D6 activity. Among 4. IARC. Tobacco smoking. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, IARC Scientific Publications, Vol. 38, pp. 221—228.Lyon, studies in which tobacco smoking was reported, those which found a France: Intemational Agency for Research on Cancer, 1986. positive effect of CYP2D6 activity on lung cancer risk included 5. Dayer, P., Leeman, T., and Striberni, R. Dextromethorphan O-demethylation in liver subjects with a higher level of tobacco smoking; the mean pack-years microsomes as a prototype reaction to monitor cytochrome P-450 dbl activity. Clin. 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Christine Bouchardy, Simone Benhamou and Pierre Dayer

Cancer Res 1996;56:251-253.

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