3）構造活性相関による遺伝毒性の予測

1 39 v onsh p;..SAR in silico SAR SAR SAR Structural Activity Relationship Approaches for Assessing GenotoxicityMasam slat establ dent fy ng .. cals .. ng ..of .. structure-act v onsh SAR .. que ..cons ..pr or t z ng ..chem cals ..for .. ficat nogen c c colog .. h for .. health,.. for.

2 Any ..of ..the ..po nts..Th ew .. stor cal ..pred ct ng ..carc nogen c ty ..and ..genotox c ty, ..the .. c ,.. ;.. v onsh SAR ,..Genotox c ty,.. ,..Sens t v ty,..Spec fic ty SAR SAR 1930 NMR 1940 Schm dt Pullman K Bay 1970 El ller DNA :Masam tsu.

3 Honma:.. yoga,..Setagaya-ku,.. ,..Japan;..Tel: ..+81-3-3700-9847;..Fax:..+81-3-3700-234 8;..E-ma l:..honma@n Natl. Inst. Health Sci., 128, 39-43 2010 Special Report 128 2010 40 Ames in vitro M llers 1 DNA 2 DNA DNA 1 M ller M ller Ashby Tennant ;..SA SAR SA DNA SA Ashby Nat 222 18 SA F Ashby nogen 18 SA Toxnet Gold/Ze ger Carc nogen Inst.

4 Santa ISSCA 698 878 Ashby SAR 65% 78% DNA M ller SAR SAR SAR SAR Ashby QSAR Quant tat DEREK QSAR ADMEWORKS B ophore

5 Mult CASE SAR (a)(b)(c)(d)(e)( )(f)(g)(h)(r)(i)(j)(q)(r)(k)(l)(m)(n)(o) (p)(o)Fig. 1 Ashby nogen ;.. ch .. are .. class f ed .. as .. structure-act ve .. pos t ve ..as ..follows:.. a .. e sulphon ds;.. b ..aromat ;.. c ..aromat ;.. d ..aromat des;.. e .. aromat d alkylam no .. group;.. f .. nes;.. g .. ;.. h .. vat ves;.. monohaloalkanes;.. j .. fam ly .. of .. ;.. k .. N-chloram nes;.. l .. prop osultones;.. m .. aromat al phat az r d vat ves;.. n ..al phat des;.. o ..der vat urethane;.. p .. trosoam nes;.. q .. aromat am nes;.. r .. al phat de. 41 206 DEREK Mult CASE ADMEWORKS Sens t v ty Spec fic ty Con-cordance DEREK ADMEWORKS Mult CASE DEREK ADMEWORKS.

6 T ve K rkland 703 in vitro , Snyder 2002 2004 Phys c ans .. 394 DEREK Mult CASE TOPKAT ADMEWORKS QSAR SAR Mult CASE TOPKAT 50% DEREK SA SAR ve SAR DEREK Mult CASE ADMEWORKS SAR Hayash SAR 3,000 SAR F SAR Table 1 Hayash.

7 ,..2005 AmesResults+-TotalSens t v ty Spec fic ty Concordance DEREK+ + + :..Mult CASE;..AWORKS:.. to be analyzed<MW 3,000 EpoxideNoYesYesNoPositiveNegativeDEREKMC ASEAWORKS=3: +ve=3: -ve 2: +veorPositiveNegativeGrayor 2 -veFig. 2 Dec s on ..tree ..for ..pr or t z ng ..chem cals ..for .. ficat on..MCASE:..Mult CASE,..AWORKS:..ADMEWORKS 128 2010 42 87% 95% 94% Appl cab l ty 55% 10 20,000 90% 18,000 9,900 18,000 in vitro in vitro SAR DNA DNA SA SAR DEREK 11 74 SA 87 209 64% 36% ve SAR In vitro

8 SAR Mekenyan 10 mulator TIMES Table 2 Hayash .. ,..2005 Comb nat +++---TotalSens t v ty Spec fic ty Concordance Ames+-Total13518294961599114* * cals,.. +++.. cab l 114/206 .Table 3 +-TotalSens t v ty Spec fic ty Concordance ChromAb+ :.. 43 TIMES QSAR OASIS Opt m Q SAR in vitro in vitro Q SAR Q SAR Q SAR M ller 2007 EPA ToxCast in vitro Q SAR 11 M ller Q SAR

9 Schm t,..O.:..Physik Chem B42,.. 1939 Pullman,.. ,..B.:..Rev Sci 3,.. 1946 M ller, ..and ..M ller, .. :..Cancer 47,.. 1981 Ames,.. ,..Cancer 53,.. 1984 Ashby,.. J.. Tennant,.. :.. Mutat Res 204,.. 1988 Ben gn ,.. ,.. C:.. Mutat Res, 659,.. 2008 Hayash ,..M.,.. Kamata,..E.,.. H rose,..A.,.. Takahash ,..M.,..Mor ta, ..T., ..and ..Ema,..M.: ..Mutat Res, 588,.. 2005 K rkland,.. D., .. Aardema,.. M., .. Henderson,.. L., .. ,..L.:..Mutat Res, 584,.. 2005 Snyder,..R., ..Pearl,..G., ..Mandakas,..Choy,..W., ..Goodsa d,..F., .. and .. Rosenblum,.. I.: .. Environ Mol Mutgen 43,.. 2004 10 Mekenyan,.. ,..D m trov,.. ,..Pavlov,.. ,.. th,.. :..Curr Pharm Des 10.

10 2004 11 Schm t, .. :.. Environ Health Perspect, 117,.. 2009