RAKOTVORNO DELOVANJE KEMIKALIJ IZ OKOLJA
0HWND)LOLSLþ
POVZETEK. 1DVWDQHN LQ UD]YRM UDND MH NRPSOHNVHQ YHþVWRSHQMVNL SURFHV 9 SULVSHYNX VR RSLVDQH ODVWQRVWLLQ RVQRYQLPHKDQL]PL UDNRWYRUQHJD GHORYDQMD NHPLNDOLM 5D]OLNXMHPR JHQR WRNVLþQHLQ QHJHQRWRNVLþQHNDUFLQRJHQHSULþHPHUJHQRWRNVLþQL SRY]URþLMR JHQHWVNHVSUHPHPEH SRWUHEQH ]D LQLFLDFLMR LQ QDSUHGRYDQMH UDND PHGWHP NR QHJHQRWRNVLþQL SRVSHãXMHMR FHOLþQR SUROLIHUDFLMR LQ YSOLYDMR SUHGYVHP QD SURPRFLMR UDND 9HþLQD RUJDQVNLK NDUFLQRJHQRY GHOXMH LQGLUHNWQRLQSRWUHEXMHMRSUHVQRYRYYPHVQHSURGXNWHNLWYRULMR'1.DGXNWHNLYNROLNRUVHQH SRSUDYLMR SRY]URþLMR PXWDFLMH LQ NURPRVRPVNH DEHUDFLMH 1HNDWHUL NDUFLQRJHQL SUHGYVHP NRYLQH LPDMR JHQRWRNVLþQH XþLQNH SUHN SRY]URþDQMD WYRUEH SURVWLK NLVLNRYLK ]YUVWL .HPLMVNL NDUFLQRJHQL SRY]URþDMR WXGL HSLJHQHWVNH VSUHPHPEH L]UDåDQMD WDUþQLK JHQRY 1D RVQRYL SR]QDYDQMHYVHKWHKODVWQRVWLODKNRVNOHSDPRGDMHL]SRVWDYOMHQRVWNHPLMVNLPNDUFLQRJHQRP SRPHPEHQQHYDUQRVWQLGHMDYQLN]DQDVWDQHNUDND
UVOD
5D]YRMUDNDMHYHþVWRSHQMVNLSURFHVYNDWHUHPVHNRSLþLMRJHQHWVNHLQHSL JHQHWVNH VSUHPHPEH NL QD NRQFX SULYHGHMR GR QDVWDQND FHOLF NL QHQDG ]RURYDQRUDVWHMRLPDMRVSRVREQRVWYGLUDQMDYVRVHGQMDWNLYDLQ]DVHYDQMD LQSRVWDQHMRNOLQLþQRSUHSR]QDYQHNRWEROH]HQ6OLND
9VWRSQMLLQLFLDFLMHQDVWDQHSRãNRGED'1.NLSULYHGHGRPXWDFLMHLQVWHP VSUHPHQLJHQHWVNL]DSLVFHOLFHQRYHMãHUD]LVNDYHSDVRSRND]DOHGDODKNR GRLQLFLDFLMHSULYHGHMRWXGL HSLJHQHWVNHVSUHPHPEHL]UDåDQMD JHQRY)D]D SURPRFLMHUDNDREVHJDVHOHNWLYQRNORQDOQRUDVWLQLFLLUDQLKFHOLFLQODKNRWUDMD YHþOHW1DVWDQHMRWXGLQDGDOMQMHJHQHWVNHVSUHPHPEHNLYID]LQDSUHGRYDQMD SULYHGHMRGRWUDQVIRUPDFLMHSUHGUDNDYLKFHOLFYPDOLJQHUDNDYHFHOLFH +DQDKDQLQ:HLQEHUJ>@VWDRSLVDODãHVWNOMXþQLKODVWQRVWLNLVRSRWUHEQH za nastanek raka:
WUDMQRVLJQDOL]LUDQMH]DFHOLþQRSUROLIHUDFLMR QHRG]LYQRVWQD]DYLUDOFHUDVWL
RGSRUQRVWQDFHOLþQRVPUW
Y]SRVWDYLWHYQHRPHMHQHVSRVREQRVWLUHSURGXNFLMHQHVPUWQRVWFHOLF VSRVREQRVWVSURåLWYHDQJLRJHQH]HWYRUEHQRYLKåLOLQ
VSRVREQRVWLQYD]LMHLQ]DVHYDQMD>@
7HVSUHPHPEHYYHOLNLPHULQDVWDQHMRNRWUH]XOWDWDNWLYDFLMHRQNRJHQRYLQ LQDNWLYDFLMH WXPRUVXSUHVRUVNLK JHQRY 2QNRJHQL UDND LQGXFLUDMR >@ FHOLFL RPRJRþDMR SURLIHUDFLMR LQ SUHåLYHWMH 1DVSURWQRSDWXPRUVXSUHVRUVNLJHQL FHOLFH ãþLWLMR SUHG VSUHPHPEDPL NL YRGLMR Y QDVWDQHN UDND >@ QD SULPHU WDNRGDSUHSUHþXMHMRSUROLIHUDFLMRDOLSDVSURåLMRSURJUDPLUDQRFHOLþQRVPUW DSRSWR]R
6OLND9HþVWRSHQMVNLPRGHOQDVWDQNDUDNDNLREVHJDLQLFLDFLMRSURPRFLMRLQQDSUHGRYDQMH
2QNRJHQL YHþLQRPD GHOXMHMR NRW GRPLQDQWQL =YHþDQD DNWLYQRVW R]LURPD L]UDåDQMHHQHJDDOHOD]DGRVWXMH]DDNWLYDFLMRVLJQDOL]LUDQMD]DYHþMRUDVWLQ SUHåLYHWMH2QNRJHQLVHDNWLYLUDMR]DUDGLQDVWDQNDWRþNRYQHPXWDFLMHSRPQR åHYDQMD VHJPHQWD NURPRVRPD NL YVHEXMH WH JHQH DOL SD WUDQVORNDFLMH QD PHVWRNLMHSRGQDG]RURPPRþQHJDSURPRWRUMD=D LQDNWLYDFLMR WXPRUVX SUHVRUVNLKJHQRYSDVHVPDWUDGDMHSRWUHEQDL]JXEDIXQNFLMHREHKDOHORY>@
=DUDGLWHJDVWDQDYDGQRSRWUHEQLGYHVWRSQML1DMSRJRVWHMHQDVWDQHWRþNRYQD PXWDFLMDYHQHPDOHOXLQL]JXEDYGUXJHP]DUDGLGHOHFLMHDOLUHNRPELQDFLMH
MEHANIZMI DELOVANJA RAKOTVORNIH KEMIKALIJ
*OHGH QD PHKDQL]HP GHORYDQMD ODKNR NHPLMVNH NDUFLQRJHQH GHOLPR QD JHQRWRNVLþQH LQ QHJHQRWRNVLþQH NDUFLQRJHQH 7DEHOD 3UYL SRY]URþDMR SRãNRGEH '1. LQ PXWDFLMH LQLFLDFLMR WHU QDSUHGRYDQMH UDND GUXJL SD VSRGEXMDMR FHOLþQR GHOLWHY Y WDUþQHP WNLYX SULVSHYDMR N ILNVDFLML PXWDFLM SRY]URþDMRVSUHPHPEHYL]UDåDQMXJHQRYLQVSUHPHPEHQDG]RUDUDVWLFHOLF SUHNGHORYDQMDQDUD]QHFHOLþQHUHFHSWRUMHQSUKRUPRQVNH$K533D5LQ SULVSHYDMRNSURPRFLMLUDND
*HQRWRNVLþQH NHPLMVNH UDNRWYRUQH VQRYL DOL NHPLMVNH NDUFLQRJHQH ODKNR UD]GHOLPR QD WLVWH NL QHSRVUHGQR UHDJLUDMR ] PROHNXOR '1. LQ WLVWH NL SRWUHEXMHMR SRSUHMãQMR SUHVQRYQR DNWLYDFLMR 3ULPHUL QHSRVUHGQLK NDUFLQR JHQRY NL QH SRWUHEXMHMR SRSUHMãQMR SUHVQRYQH DNWLYDFLMH VR HWLOHQ RNVLG IRUPDOGHKLG WHU ãWHYLOQL NHPRWHUDSHYWLNL >@ ,QGLUHNWQL NDUFLQRJHQL DOL SURNDUFLQRJHQLSDVHPRUDMRQDMSUHMSUHVQRYLWLGDQDVWDQHMRUHDNWLYQLYPHVQL SURGXNWL NL UHDJLUDMR ] '1. LQ SRY]URþLMR SRãNRGEH 2FHQMHQR MH GD MH RNURJþHWUWLQDNDUFLQRJHQRYWDNãQLKNLGHOXMHMRQHSRVUHGQRWULþHWUWLQHSD MHSURNDUFLQRJHQRY>@
7DEHOD=QDþLOQRVWLJHQRWRNVLþQLKLQQHJHQRWRNVLþQLKNDUFLQRJHQRY
*HQRWRNVLþQLNDUFLQRJHQL x UHDJLUDMR]'1.
x VRPXWDJHQL
x ODKNRGHOXMHMRNRWSRSROQLNDUFLQRJHQL x WXPRULJHQRVWMHRGYLVQDRGRGPHUND
x QLPRJRþHGRORþLWLPHMQHYDUQHGR]HL]SRVWDYOMHQRVWLQLPDMRSUDJDGHORYDQMD x GHOXMHMRYYVHKID]DKQDVWDQNDLQUD]YRMDUDND
1HJHQRWRNVLþQLNDUFLQRJHQL x QHUHDJLUDMR]'1.
x QLVRPXWDJHQL
x YSOLYDMRQDL]UDåDQMHJHQRY x LPDMRSUDJGHORYDQMD
x XþLQNLVRUHYHU]LELOQLRGYLVQLRGRGPHUNDLQWUDMDQMDL]SRVWDYOMHQRVWL x WXPRULJHQRVWMHRGYLVQDRGRGPHUND
x GHOXMHMRYID]LSURPRFLMHUDND
.HPLMVNLNDUFLQRJHQLSRY]URþDMRSRãNRGEH'1.SUHNNRYDOHQWQHYH]DYHQD UHDNWLYQD PHVWD PROHNXOH '1. SUHN RNVLGDWLYQLK SRãNRGE '1. ]DUDGL SRY]URþDQMD WYRUEH SURVWLK NLVLNRYLK ]YUVWL 526 LQDOL SUHN SRY]URþDQMD HSLJHQHWVNLKVSUHPHPE>@.HPLMVNLNDUFLQRJHQLR]LURPDQMLKRYLSUHVQRYNL PRUDMR ELWL WXGL VSRVREQL YVWRSLWL Y RUJDQL]HP LQ FHOLFH NDU SRPHQL GD PRUDMR ELWL DOL OLSRILOQL GD MH RPRJRþHQ SDVLYQL WUDQVSRUW DOL SD PRUDMR Y FHOLFH YVWRSLWL ] DNWLYQLP WUDQVSRUWRP .RPSOHNVQRVW GHORYDQMD NHPLMVNLK NDUFLQRJHQRYYSURFHVXQDVWDQNDLQUD]YRMDUDNDMHSULND]DQDQD6OLNL
*HQRWRNVLþQLNHPLMVNLNDUFLQRJHQLVHNRYDOHQWQRYHåHMRQDQXNOHRWLGH'1.
SULþHPHUQDVWDQHDGXNW'1.DGXNWHODKNRUD]GHOLPRYGYHJODYQLVNXSLQL L PDMKQH ] QDMKQR PROHNXOVNR PDVR LQ LL ]DMHWQH PDNURPROHNXODUQH DGXNWH 6DP '1.DGXNW QH SRY]URþL PXWDFLMH UD]OLþQL DGXNWL SD LPDMR UD]OLþQRVSRVREQRVWSRY]URþDQMDPXWDFLM9HþLQDNHPLNDOLMNLWYRULMRDGXNWH MH PRþQR HOHNWURILOQLKQHSRODUQH PROHNXOH V SR]LWLYQLP QDERMHP HOHNWURILO QHJDFHQWUDNLWYRULMRQHUHYHU]LELOQHVWDELOQHDGXNWHQDPRþQLKQXNOHRILOQLK PHVWLK QHSRODUL]LUDQD PHVWD ] PRþQLP QHJDWLYQLP QDERMHP Y PROHNXOL '1. âLENLHOHNWURILOLSRODUL]LUDQH PROHNXOH ] GHOQLPSR]LWLYQLP QDERMHP NRW VR DOGHKLGL LQ NHWRQL SD UHYHU]LELOQR UHDJLUDMR V ãLENLPL QXNOHILOQLPL PHVWLYPROHNXOL'1.>@7HNHPLMVNHUD]OLNHVRSRPHPEQHVDMVRVWDELOQL DGXNWL SRYH]DQL ] YHþMR PXWDJHQRVWMR =D UDNRWYRUQL SRWHQFLDO SD MH SR PHPEQRWXGLYH]DYQRPHVWRDGXNWDQDQXNOHRWLGVDMVRGRORþHQDYH]DYQD PHVWDEROMPXWDJHQD
Absorpcija
6OLND0HWDEROLþQDDNWLYDFLMDNHPLMVNLKNDUFLQRJHQRYLQQMLKRYLJHQRWRNVLþQLLQ QHJHQRWRNVLþQLXþLQNL
Majhni, nizkomolekularni DNK-adukti najpogosteje nastanejo po alkilaciji kovalentne vezave funkcionalne alkilne skupine na molekulo DNK. Na splošno je alkilacija dušika nukleinske baze manj mutagena od alkilacije NLVLND7LDGXNWLODKNRGHVWDELOL]LUDMR'1.WDNRGDQDVWDQHMRQHNRGLUDMRþD DED]LþQD PHVWD DOL SD ODKNR SRY]URþLMR YJUDGQMR QDSDþQH ED]H >@ 9 WR skupino spadajo N-nitrozo spojine in nitrozamini, ki nastajajo tudi endogeno, SD WXGL ERMQLVWUXS LSHULW 1HNDWHUH DONLOLUDMRþHNHPLNDOLMH SD SRY]URþLMR QD VWDQHNSUHþQLKYH]LPHGYHULJDPD'1.NL]DYUHMRWUDQVNULSFLMRLQUHSOLNDFLMR '1. >@ LQ ODKNRPHG SRSUDYOMDQMHPSRY]URþLMR QDVWDQHNGYRYHULåQLK SUH ORPRY'1.>@7DNRGHOXMHQDSULPHUNHPRWHUDSHYWLNFLVSODWLQ
9HOLNLDGXNWLSDYHþLQRPDXVWDYLMRWUDQVNULSFLMRLQUHSOLNDFLMR'1.LQSRY]UR þDMRSUHORPHNURPRVRPRYLQYHOLNHGHOHFLMHNDUSULYHGHGRL]JXEHKHWHUR]L JRWQRVWL>@(SLGHPLRORãNHLQHNVSHULPHQWDOQHUD]LVNDYHSRWUMXMHMRSRYH]DYH PHG WYRUER '1.DGXNWRY LQ QDVWDQNRP UDND >@ 9 WR VNXSLQR VSDGD YHþLQD JHQRWRNVLþQLK RUJDQVNLK NDUFLQRJHQRY WLSLþQL SULPHUL VR EHQ]RD SLUHQ LQ GUXJL SROLDURPDWVNL RJOMLNRYRGLNL KHWHURFLNOLþQL DURPDWVNL DPLQL DIODWRNVLQ%LGU
1HNDWHUH NHPLNDOLMH DOL QMLKRYLSUHVQRYNLSRY]URþDMR RNVLGDWLYQH SRãNRGEH '1. NL VR SRJRVWR SRVOHGLFD GHORYDQMD VWUDQVNLK UHDNWLYQLK SURGXNWRY NL QDVWDMDMR Y SUHVQRYL 2NVLGDWLYQH SRãNRGEH VR RGJRYRUQH ]D YHOLN GHO PXWDFLM >@ 3UHWHåQR MLK SRY]URþDMR SURVWH UHDNWLYQH ]YUVWL UHDNWLYQH PROHNXOH DOL LRQL ] QHSDUQLPL HOHNWURQL NRW VR UHDNWLYQH NLVLNRYH ]YUVWL Reactive Oxygen Species 526 >@ 1DVWDQHN 526 MH SRVOHGLFD QHSR VUHGQHJD GHORYDQMD NHPLNDOLM DOL SD SRVUHGQHJD SUHN SRY]URþDQMD YQHWLM 526SRY]URþLMRUD]QHPROHNXODUQHSRãNRGEHYNOMXþQRVSUHORPLYHULJ'1.
LQNRYDOHQWQLPLYH]PLQDQXNOHLQVNH ED]H>@'LRNVLQL LQ SROLNORULUDQLELIHQLOL VRSULPHUNDUFLQRJHQRYNLSRY]URþDMRPXWDFLMHVWYRUMHQMHP526>@
3ROHJ ãWHYLOQLK RUJDQVNLK VQRYL VR UDNRWYRUQH WXGL QHNDWHUH NRYLQH NL MLK 0HGQDURGQDDJHQFLMD]DUD]LVNRYDQMHUDND,$5&XYUãþDPHGNDUFLQRJHQH LQ YHUMHWQR NDUFLQRJHQH ]D OMXGL 0HGQMH VSDGDMR NDGPLM QLNHOM NREDOW VYLQHF YDQDGLM EHULOLM DU]HQ LQ NURP 0HKDQL]PL UDNRWYRUQHJD GHORYDQMD NRYLQ VR PDQM UD]LVNDQLNRW PHKDQL]PL GHORYDQMD RUJDQVNLK VSRMLQ 0HKD QL]PLGHORYDQMHNRYLQVHVLFHUUD]OLNXMHMRYHþLQRPDSDSRY]URþDMRJHQHWVNH LQ HSLJHQHWVNH VSUHPHPEH VSUHPHPEH FHOLþQH SUROLIHUDFLMH LQ SUHVQRYH VSUHPHQMHQHVLJQDOQHSRWLWHUWYRUER526>@.DGPLMDU]HQQLNHOMNREDOW LQVYLQHFSDWXGLNRPSHWLWLYQRLQKLELUDMRHQFLPHVFLQNRYLPREURþHPPHG NDWHUHVSDGDMRãWHYLOQLHQFLPLYNOMXþHQLYSRSUDYOMDQMHSRãNRGE'1.>@
3RVOHGLFDMHLQKLELFLMDSRSUDYLODSRãNRGE'1.LQVWHPYHþMDYHUMHWQRVWGD SRãNRGEHSULYHGHMRGRPXWDFLM
9QDVWDQHNLQUD]YRMUDNDQLVRYNOMXþHQHOHPXWDFLMHWDUþQLKJHQRYNLL]YLUDMR L] SRãNRGE '1. 1RYHMãH UD]LVNDYH NDåHMR GD LPDMR SUL WHP SURFHVX SRPHPEQR YORJR HSLJHQHWVNH VSUHPHPEH (SLJHQHWVNH VSUHPHPEH VR VWDELOQHGHGQHLQSULYHGHMRGRVSUHPHPEYL]UDåDQMXJHQRY>@9HOLNRMH GRND]RY GD L]SRVWDYOMHQRVW RNROMVNLP GHMDYQLNRP VSUHPHQL HSLJHQHWVNR UHJXODFLMRJHQRPDþHSUDYPHKDQL]PLãHQLVRSRYVHPUD]LVNDQL(SLJHQHW VNHVSUHPHPEHGHOXMHMRQDL]UDåDQMHJHQRYSULþHPHU]DSRUHGMD'1.QLVR VSUHPHQMHQD=DVHGDMVWDQDMEROMHUD]LVNDQDPHKDQL]PDPHWLODFLMD'1.LQ PRGLILNDFLMDKLVWRQRY
0HWLODFLMD'1.MHQRUPDOHQIL]LRORãNLSURFHVSULNDWHUHPVHPHWLOQDVNXSLQD
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3UHWHåQRVRPHWLOLUDQL&S*GLQXNOHRWLGLNLVRSRJRVWRORFLUDQLYSURPRWRUVNLK UHJLMDKJHQRYWDNRLPHQRYDQL&S*RWRNLCpG islands&*,0HWLOLUDQL&*, SUDYLORPD ]DYUHMR WUDQVNULSFLMR JHQD 6SUHPHQMHQL Y]RUFL PHWLOLUDQRVWL VR ]QDþLOQL]DYVHYUVWHUDND0HWLODFLMD'1.GHOXMHQDUD]YRMUDNDQDWULJODYQH QDþLQHLVSORãQDKLSRPHWLODFLMDLLKLSHUPHWLODFLMDSURPRWRUMHYLQLLLLQGXN FLMD WRþNRYQLK PXWDFLM >@ 6SORãQD KLSRPHWLODFLMD MH ]JRGQML GRJRGHN SUL UD]YRMXUDNDNLODKNRSRY]URþLYHþMHL]UDåDQMHRQNRJHQRYSRYH]DQDSDMH WXGL]L]JXERJHQRPVNHVWDELOQRVWL>@0HWLODFLMDSURPRWRUMDMHSRYH]DQD]
XWLãDQMHPL]UDåDQMD JHQRY LQ VHVPDWUD GDMH JODYQL PHKDQL]HPLQDNWLYD FLMH WXPRUVXSUHVRUVNLK JHQRY >@ 2FHQMHQR MH GD LPD YHþLQD WXPRUMHY
± KLSHUPHWLOLUDQLK SURPRWRUVNLK UHJLM >@ âWHYLOQH RNROMVNH LQ SRNOLFQH L]SRVWDYOMHQRVWL VR SRYH]DQH V VSUHPHPEDPL PHWLODFLMH '1.
3RY]URþDMR MLK WDNR LRQL]LUDMRþD VHYDQMD NRW ãWHYLOQH RUJDQVNH LQ DQRUJDQ VNH NHPLNDOLMH RG NDWHULK LPDMR ãWHYLOQH SOHLRWURSQH XþLQNH ýH PHWLOLUDQL
&S*QLVRSRSUDYOMHQLODKNRSRY]URþLMRWXGLWRþNRYQHPXWDFLMH
1DL]UDåDQMHJHQRYGHOXMHMRWXGLVSUHPHPEHKLVWRQRYNDWHULKSRVOHGLFHVR VSUHPHPEH]JUDGEHNURPDWLQDNLQHSRVUHGQRYSOLYDQDWUDQVNULSFLMRJHQRY UHSOLNDFLMR'1.SRSUDYOMDQMH'1.LQRUJDQL]DFLMRNURPRVRPRY>@+LVWRQL VRSURWHLQLNLMLKVHVWDYOMDRVHPSRGHQRWRNURJNDWHULKMHRYLWD'1.LQWYRUL ]JUDGER NL VH LPHQXMH QXNOHRVRP >@ 6SUHPHPEH ODKNR QDVWDQHMR QD UD]OLþQLK SRGHQRWDK LQ YNOMXþXMHMR DFHWLODFLMR PHWLODFLMR IRVIRULODFLMR DOL JOL NR]LODFLMR QD 1NRQFLK SURWHLQRY NL ãWUOLMR L] QXNOHRVRPD >@ $FHWLODFLMD KLVWRQRY MH SRYH]DQD ] DNWLYDFLMR WUDQVNULSFLMHPHGWHPNR VR GUXJH VSUH PHPEHPDQMUD]LVNDQH5D]LVNDYHVRSRND]DOHGDVRRNROMVNHLQSRNOLFQH L]SRVWDYOMHQRVWLSRYH]DQHVVSUHPHPEDPLKLVWRQRYSUHGYVHPL]SRVWDYOMH QRVW NRYLQDP .URP QD SULPHU SRY]URþL XWLãDQMH JHQRY ] GHORYDQMHP QD HQFLPHNLNDWDOL]LUDMRDFHWLODFLMRKLVWRQRY>@
RAKOTVORNO DELOVANJE KADMIJA
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Slika 3. Mehanizem karcinogenega delovanja kadmija prek indukcije poškodb DNK, inhibicije SRSUDYOMDOQLKPHKDQL]PRY'1.QDG]RUDFHOLþQHUDVWLLQDSRSWR]HVWLPXODFLMHFHOLþQH
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3. Knudson Jr AG. Mutation and cancer: Statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68 (4): 820–3.
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