Tobacco-Specific Carcinogens Genetic Factors That Increase the Risk for Bronchial Carcinoma

of฀NNK฀in฀humans฀and฀animals฀are฀identical.฀NNK฀doses฀absorbed฀by฀humans฀are฀dei- nitely฀carcinogenic฀in฀animal฀experiments.฀Prior฀to฀binding฀to฀DNA,฀both฀nitrosamines฀ require฀ activation฀ a-methyl฀ or฀ a-methylene฀ hydroxylation,฀ pyridine-N-oxidation฀ by฀ CYP-mediated฀reactions฀and฀glucuronidation฀ [64,฀65] .฀The฀alcohol฀from฀NNK฀is฀excreted฀ in฀the฀urine฀and฀serves฀as฀an฀indicator฀for฀NNK฀exposure. The฀AA,฀including฀4-aminobiphenyl,฀are฀compounds฀that฀play฀a฀particular฀role฀in฀the฀ development฀of฀carcinoma฀of฀the฀bladder฀ [66] ฀and฀therefore,฀will฀not฀be฀discussed฀further฀ in฀the฀present฀context. DNA฀damage฀is฀also฀produced฀as฀a฀result฀of฀oxidation฀processes฀and฀by฀lipid฀peroxida- tion.฀Inhaled฀material฀from฀tobacco฀contains฀oxygen฀and฀nitrogen฀groups,฀which฀react฀with฀ the฀various฀body฀tissues฀in฀smokers.฀Consequently,฀oxidative฀DNA฀damage฀due฀to฀prod- ucts฀formed฀by฀lipid฀peroxidation฀malondialdehyde,฀crotonaldehyde,฀trans-4-OH-2-฀nonenal฀ is฀commonly฀found฀in฀the฀respiratory฀tract฀tissues฀of฀smokers.฀These฀metabolites฀are฀epoxi- dised฀by฀CYP-mediated฀reactions฀and฀form฀promutagenic฀DNA฀adducts฀in฀human฀tissue฀ [40,฀ 67,฀ 68] ,฀ leading฀ to฀ an฀ increased฀ cancer฀ risk฀ for฀ the฀ upper฀ respiratory฀ tract฀ [41] .฀ Chewing฀tobacco฀with฀or฀without฀betel฀produces฀cancers฀in฀the฀oral฀cavity฀ [69] .

5.2.3.2 The Cytochrome P450 and GST System and Carcinogenesis

Current฀epidemiological฀research฀into฀carcinogenesis฀in฀the฀lung฀indicates฀that฀several฀pop- ulations฀are฀at฀risk฀for฀the฀development฀of฀lung฀cancer,฀especially฀smokers฀and฀workers฀ exposed฀to฀toxic฀substances.฀One฀genetic฀factor฀that฀deserves฀particular฀mention฀in฀this฀ context฀is฀the฀induction฀of฀aryl฀hydrocarbon฀hydroxylase฀CYP1A1;฀AHH.฀This฀enzyme฀ transforms฀the฀PAH฀produced฀by฀cigarette฀smoke฀into฀compounds฀that฀are฀highly฀carcino- genic฀ [70] .฀In฀addition,฀oxidation฀processes฀are฀catalysed฀by฀the฀CYP450฀system฀and฀using฀ debrisoquine-4-hydroxylation฀ CYP2D6฀ as฀ a฀ model฀ reaction,฀ a฀ clear฀ distinction฀ can฀ be฀ drawn฀between฀lung฀cancer฀patients฀and฀matched฀controls฀ [71–73] .฀Where฀there฀is฀extensive฀ hydroxylation฀of฀the฀“model฀substance”฀debrisoquine,฀the฀risk฀for฀the฀development฀of฀lung฀ cancer฀is฀simultaneously฀increased.฀To฀date,฀however,฀there฀are฀no฀routine฀tests฀for฀the฀pro- phylactic฀identiication฀of฀such฀risk฀factors.฀As฀shown฀by฀the฀data฀summarised฀in฀Fig.฀ 5.4 ,฀ the฀renal฀excretion฀of฀carcinogens฀is฀higher฀in฀smokers฀than฀in฀non-smokers,฀with฀slight฀dif- ferences฀detected฀in฀terms฀of฀residential฀environment฀suburban฀or฀rural฀ [56] .฀Several฀stud- ies฀have฀been฀conducted฀in฀patients฀affected฀by฀these฀problems฀ [66] ฀and฀the฀key฀inding฀is฀ that฀metabolites฀of฀these฀inhaled฀tobacco฀products฀form฀adducts฀with฀DNA฀Fig.฀ 5.4 . The฀CYP฀system฀plays฀a฀central฀role฀in฀the฀metabolism฀or฀activation฀of฀carcinogens฀ [68,฀ 74–77] .฀Case-control฀studies฀have฀revealed฀associations฀between฀tobacco฀smoke฀and฀can- cer฀risks฀for฀the฀lungs,฀larynx,฀mouth,฀oesophagus,฀kidneys,฀urinary฀system฀and฀breasts. CYP1A1:฀PAH฀and฀AA฀are฀activated฀by฀the฀enzyme.฀Approximately฀10฀of฀Caucasians฀ have฀a฀highly฀inducible฀form฀of฀CYP1A1฀also฀known฀as฀B[a]P-hydroxylase,฀in฀conjunc- tion฀with฀an฀increased฀risk฀for฀tumours฀of฀the฀bronchi,฀larynx฀and฀oral฀cavity฀ [78] .฀Four฀ different฀forms฀of฀the฀cytochrome฀enzyme฀1A1฀have฀been฀described฀to฀date฀Table฀ 5.2 ,฀ though฀regrettably฀several฀nomenclatures฀are฀in฀use.฀The฀inducibility฀of฀CYP1A1฀corre- lates฀with฀the฀occurrence฀of฀bronchial฀carcinoma฀ [80] ,฀with฀the฀m2฀mutant฀Ile-→−Val฀ being฀twice฀as฀inducible฀as฀the฀m1฀mutant฀ [81] .฀Smokers฀with฀the฀m2฀mutant฀have฀more฀ DNA฀adducts฀in฀their฀leucocytes฀than฀smokers฀without฀this฀mutant฀ [82] .฀These฀adducts฀are฀ also฀increased฀in฀the฀cord฀venous฀blood฀of฀neonates฀with฀CYP1A1-MspI฀polymorphism฀ [82] .฀ B[a]PDE฀ concentration฀ and฀ PAH-DNA฀ adducts฀ correlate฀ positively฀ with฀ enzyme฀ activity฀ in฀ the฀ parenchymal฀ lung฀ tissue฀ of฀ smokers฀ [36] .฀ Homozygous฀ CYP1A1-MspI฀ alleles฀are฀observed฀more฀rarely฀in฀Caucasians฀than฀in฀Japanese฀ [83] . Associations฀with฀CYP1A1฀activity฀have฀been฀demonstrated฀in฀more฀than฀20฀studies฀in฀ different฀ethnic฀populations฀see฀Table฀ 5.3 .฀According฀to฀studies฀from฀Japan,฀the฀lung฀can- cer฀risk฀was฀demonstrated฀with฀both฀m1฀and฀m2฀mutants฀ [85] .฀The฀CYP1A1฀phenotype฀was฀ important฀in฀terms฀of฀the฀development฀of฀SCCs฀only฀in฀moderate฀smokers฀ [88] .฀The฀results฀ were฀not฀corroborated฀in฀Norwegian,฀Finnish,฀Swedish฀and฀US฀populations,฀a฀inding฀that฀ was฀possibly฀attributable฀to฀the฀smaller฀occurrence฀of฀the฀m1฀allele฀in฀Caucasians.฀Studies฀ conducted฀in฀a฀mixed฀US฀population฀and฀in฀French฀patients฀showed฀no฀evidence฀of฀a฀pre- ferred฀allele฀m1฀or฀m2฀for฀increased฀cancer฀prevalence.฀In฀one฀study,฀individuals฀with฀the฀ m3฀mutation฀m1m1,฀m2฀had฀an฀increased฀AC฀risk฀with฀an฀OR฀of฀8.4฀ [97] ,฀whereas฀other฀ cancer฀types฀did฀not฀occur฀with฀increased฀frequency฀Table฀ 5.3 ฀ [30,฀97–100] .฀Where฀the฀ m1฀and฀m2฀variants฀of฀CYP1A1฀occurred฀in฀combination฀with฀the฀GSTM1฀00฀genotype,฀ there฀was฀an฀increased฀incidence฀of฀SCC฀in฀Japanese฀subjects฀ [63,฀85,฀101] . CYP1A2:฀ This฀ enzyme฀ activates฀ numerous฀ procarcinogens฀ from฀ tobacco,฀ preferen- tially฀ aromatic฀ and฀ heterocyclic฀ amines,฀ and฀ metabolises฀ nicotine.฀ The฀ sequence฀ of฀ CYP1A2฀is฀72฀identical฀with฀that฀of฀CYP1A1.฀However,฀it฀is฀formed฀principally฀in฀the฀ liver฀and฀to฀a฀very฀much฀smaller฀extent฀in฀the฀lungs฀ [102] .฀The฀enzyme฀is฀of฀marginal฀ importance฀for฀an฀increased฀risk฀of฀lung฀cancer. CYP2D6:฀This฀enzyme฀metabolises฀debrisoquine฀and฀poor฀metabolisers฀PMs฀have฀a฀ lesser฀ risk฀ for฀ the฀ development฀ of฀ lung฀ cancer฀ than฀ extensive฀ metabolisers฀ EMs฀ [71] .฀ However,฀the฀enzyme฀also฀activates฀NNK฀and฀metabolises฀nicotine฀ [103] .฀Associations฀evi- dently฀exist฀between฀nicotine฀dependence฀and฀metaboliser฀status฀ [104] .฀An฀increased฀lung฀ cancer฀risk฀has฀been฀demonstrated฀in฀EMs฀ [63,฀93,฀105–107] ,฀whereas฀two฀meta-analyses฀ have฀rejected฀such฀an฀association฀on฀the฀basis฀of฀the฀data฀reviewed฀ [22,฀107,฀108] . CYP2E1:฀CYP2E1,฀which฀is฀inducible฀by฀ethanol฀and฀numerous฀other฀agents,฀is฀capa- ble฀ of฀ metabolising฀ NNK,฀ NNN฀ and฀ other฀ soluble฀ nitrosamines฀ from฀ tobacco฀ smoke.฀ Structural฀ enzyme฀ variants฀ are฀ less฀ important฀ for฀ an฀ increased฀ lung฀ cancer฀ risk฀ in฀ Caucasians,฀with฀only฀2฀out฀of฀11฀studies฀showing฀such฀a฀inding฀ [63,฀109,฀110] .฀RsaI฀and฀ DraI฀polymorphisms฀of฀CYP2E1฀have฀not฀been฀shown฀to฀correlate฀with฀the฀development฀ of฀SCC;฀where฀these฀enzyme฀variants฀were฀present,฀there฀was฀a฀tenfold฀reduction฀in฀the฀ Polymorphism Point฀mutation Systematic฀nomenclature฀ for฀the฀mutation Wild฀type฀allele,฀m1 None wt MspI฀allele,฀3′,฀non-coding฀region,฀m2 6,235฀T→C m1 Ile→Val,฀exon฀7,฀codon฀462 4,889฀A→G m2 Afro-American-speciic฀allele,฀intron฀7 5,639฀T→C m3 Thr→Asn,฀exon฀7,฀codon฀461 4,887฀C→A m4 Table 5.2 ฀฀฀Overview฀of฀CYP1A1฀subforms฀ [79]