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3

Polκ CYP [a]

[a] BaP DNA

DNA Polκ

BaP Polκ

BaP CYP1A α- ANF BaP

Polκ CYP Polκ ANF

Polκ BaP

ANF

BaP BaP

A

[a] BaP

(1) BaP DNA

DNA TLS

(2) 、 Polη Polι Polκ

TLS (3)

Polη Polι Polκ TKO

WT

BaP WT

S9 mix 50 µM

S9 mix

IC50=13.5 µM TKO

S9 mix BaP

IC50=0.25 µM S9 mix

WT IC50=4.8

µM TKO BaP

Polκ

BaP in

vitro CYP

CYP

BaP CYP

(4) CYP1A1

HRN in vivo

BaP CYP

(5, 6) TLS

BaP DNA

CYP BaP TLS

B.

B-1. Polk

Polκ DNA

Polκ Polk+/-

C57BL6J Polk+/-

SPF CE-2 30

kGy

24±1 55±5

18 / 12

(2)

4

1-6 1

Polk-/-

Polk+/+ Polk+/-

B-2. Polk+/+ Polk-/- BaP

ANF

1 6 7 , 6 12

BaP

0% 0.003%

0.01% CYP1A1

α ANF (7)

40

1

10

B-3.

0.5 mm 1

0 /

B-4.

Dunnett

1 Tukey-Kramer

C.

C-1. Polk

Polk+/- 56 319

Polk+/+ Polk-/- Polκ

41

1 6 ×6

6 22

40

C-2. Polk+/+ Polk-/- BaP

ANF

0.003% 0.01%

BaP 0.1% ANF 4

0.003% 0.01% BaP

0.1% ANF

36 Polκ

0.01% BaP + 0.1% ANF 1

(3)

5 37

0.01% BaP + 0.1% ANF 1

1.3 cm×1.0 cm×0.5 cm

2。 38 0.003% BaP + 0.1% ANF 1

9 33 Polκ

0.01% BaP + 0.1% ANF 24

37 0.003% BaP +

0.1% ANF Table 1, Fig. 1

BaP ANF

。 40

BaP BaP

Fig. 2 0.01% BaP 0.01% BaP +ANF

Polκ 0.01% BaP

0.01% BaP +ANF

0.01% BaP 0.01% BaP +ANF

Polκ 0.01% BaP 0.01% BaP

+ANF

Table 2 1

0.01% BaP + ANF

ANF 1

+ +

0.01% BaP

Polκ 0.01% BaP + ANF

ANF 0.01% BaP

ANF 0.01% BaP + ANF

Table 3, Figure 3 D.

BaP ANF Polκ

40

3 BaP + ANF

BaP + ANF

BaP Polκ

0.01% BaP + 0.1% ANF 9

33 0.003% BaP +

0.1% ANF 24 37

ANF BaP

BaP

0.003% BaP

Polκ

。 0.01%

BaP

Polκ 1。

ANF 0.003%BaP + ANF

。 1

。 Polκ

0.01% BaP + ANF 0.01% BaP Polκ

CYP1A ANF BaP

BaP CYP1A1

in

(4)

6

vitro CYP1A1

BaP (8)

CYP1A1 BaP

Polκ

0.01% BaP 0.01% BaP + ANF

0.01%

BaP + ANF

Polκ 0.01% BaP + ANF

Polκ BaP

Benzo[a]pyrene dioletopoxide BPDE Polκ

BaP

(9) Polκ BaP

Polκ

Polκ BPDE Polκ BaP DNA

Polκ Polκ

E.

CYP1A ANF

BaP

Polκ BaP BaP

1. (2007) .

2. Friedberg,E.C., Wagner,R. and Radman,M. (2002) Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science, 296, 1627–

1630.

3. Ohmori,H., Friedberg,E.C., Fuchs,R.P., Goodman,M.F., Hanaoka,F., Hinkle,D.C., Kunkel,T.A., Lawrence,C.W., Livneh,Z., Nohmi,T., et al. (2001) The Y-family of DNA polymerases. Mol. Cell, 8, 7–8.

4. IARC Working Group on the Evaluation of Carcinogenic Risk to Humans (2012) BENZO[a]PYRENE. IARC Monogr. Eval.

Carcinog. Risks Hum.

5. Uno,S. (2006) Oral Benzo[a]pyrene in Cyp1 Knockout Mouse Lines: CYP1A1 Important in Detoxication, CYP1B1 Metabolism Required for Immune Damage Independent of Total-Body Burden and Clearance Rate. Mol. Pharmacol., 69, 1103–1114.

6. Arlt,V.M., Stiborová,M., Henderson,C.J., Thiemann,M., Frei,E., Aimová,D., Singh,R., Gamboa da Costa,G., Schmitz,O.J., Farmer,P.B., et al. (2008) Metabolic activation of

benzo[a]pyrene in vitro by hepatic cytochrome P450 contrasts with detoxification in vivo:

experiments with hepatic cytochrome P450 reductase null mice. Carcinogenesis, 29, 656–

665.

7. Hodek,P., Fousova,P., Brabencova,E.,

Moserová,M., Pavek,P., Anzenbacherova,E., Brotanek,J., Hudecek,J., Frei,E. and Stiborová,M.

(2014) Effect of dihydromyricetin on benzo[a]pyrene activation in rats. Neuro Endocrinol. Lett., 35 Suppl 2, 158–168.

8. Uno,S., Dalton,T.P., Derkenne,S., Curran,C.P., Miller,M.L., Shertzer,H.G. and Nebert,D.W.

(2004) Oral Exposure to Benzo[a]pyrene in the Mouse: Detoxication by Inducible Cytochrome P450 Is More Important Than Metabolic Activation. Mol. Pharmacol., 65, 1225–1237.

9. Ogi,T., Shinkai,Y., Tanaka,K. and Ohmori,H.

(2002) Polκ protects mammalian cells against the lethal and mutagenic effects of benzo[a]pyrene.

Proc. Natl. Acad. Sci. U.S.A., 99, 15548–15553.

参照

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