Protective role of metallothionein in benzo[a]pyrene-induced DNA damage.
Metallothionein (MT) is known to reduce chemical carcinogenesis. Carcinogenesis induced by benzo[a]pyrene (B[a]P) which is an environmental chemical carcinogen is related to DNA adduct formation and oxidative damage through metabolic activation. Ten-week-old male MT-I/II null mice and wild-type mice were given a single injection of B[a]P (250 mg/kg, p.o.), and B[a]P-induced DNA damage was evaluated at 6-48 hr later. The frequencies of micronucleated reticulocytes (MNRET) in MT-I/II null mice were significantly increased compared with that of wild-type mice at 48 hr after B[a]P administration. At 48 hr after B[a]P administration, comet scores were significantly increased in MT-I/II null mice but not in wild-type mice. 8-Hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, was significantly increased in liver of MT-I/II null mice at 6 and 12 hr after B[a]P administration, although that of wild-type mice was only slightly changed. Because cytochrome P450 (CYP) plays a major role in the process of B[a]P metabolic activation, we attempted to reveal the effect of MT on metabolic activation of B[a]P. Although CYP1A activities were elevated in the livers of MT-I/II null mice and wild-type mice treated with B[a]P, it was not different between both strains of mice. In addition, MT levels in the livers of wild-type mice were significantly increased by the B[a]P treatment, whereas MT was not detected in livers of MT-I/II null mice with or without B[a]P treatment. These results demonstrate that MT acts as an endogenous defensive factor against B[a]P-induced DNA damage.
Takaishi
Masaki
M
Laboratory of Hygienics, Gifu Pharmaceutical University, Gifu City, Gifu, Japan.
Sawada
Masumi
M
Shimada
Akinori
A
Suzuki
Junko S
JS
Satoh
Masahiko
M
Nagase
Hisamitsu
H
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D009152:Mutagenicity Tests
D002274:Carcinogens, Environmental; D001564:Benzo(a)pyrene; D008668:Metallothionein; D019363:Cytochrome P-450 CYP1A1; D003849:Deoxyguanosine