Light-dependent mutagenesis by benzo[a]pyrene is mediated via oxidative DNA damage.
Benzo[a]pyrene (B[a]P) is an environmental carcinogenic polycyclic aromatic hydrocarbon (PAH). Mammalian enzymes such as cytochrome P-450s and epoxide hydrase convert B[a]P to reactive metabolites that can covalently bind to DNA. However, some carcinogenic compounds that normally require metabolic activation can also be directly photoactivated to mutagens. To examine whether B[a]P is directly mutagenic in the presence of light, we exposed Salmonella typhimurium strains with different DNA repair capacities to B[a]P and white fluorescent light at wavelengths of 370-750 nm. B[a]P plus light significantly enhanced the number of His+ revertants. Mutagenesis was completely light-dependent and required no exogenous metabolic activation. The order of mutability of strains with different DNA repair capacities was strain YG3001 (uvrB, mutMST) >> strain TA1535 (uvrB) > strain YG3002 (mutMST) > strain TA1975. The uvrB gene product is involved in the excision repair of bulky DNA adducts, and the mutMST gene encodes 8-oxoguanine (8-oxoG) DNA glycosylase, which removes 8-oxoG from DNA. Introduction of a plasmid carrying the mOgg1 gene that is the mouse counterpart of mutMST substantially reduced the light-mediated mutagenicity of B[a]P in strain YG3001. B[a]P plus light induced predominantly G:C --> T:A and G:C --> C:G transversions. We propose that B[a]P can directly induce bulky DNA adducts if light is present, and that the DNA adducts induce oxidative DNA damage, such as 8-oxoG, when exposed to light. These findings have implications for the photocarcinogenicity of PAHs.
Kim
Su-Ryang
SR
Division of Genetics and Mutagenesis, National Institute of Health Sciences, Tokyo, Japan.
Kokubo
Kiyoko
K
Matsui
Keiko
K
Yamada
Noriyo
N
Kanke
Yusuke
Y
Fukuoka
Masamichi
M
Yamada
Masami
M
Nohmi
Takehiko
T
D000818:Animals; D001564:Benzo(a)pyrene / Q000737:chemistry*; D002273:Carcinogens / Q000737:chemistry*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D018736:DNA Adducts; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004252:DNA Mutational Analysis; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D006639:Histidine / Q000737:chemistry; D008027:Light; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D016296:Mutagenesis; D009153:Mutagens; D009154:Mutation; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry; D017382:Reactive Oxygen Species; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000528:radiation effects; D017422:Sequence Analysis, DNA
D002273:Carcinogens; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D009153:Mutagens; D011084:Polycyclic Aromatic Hydrocarbons; D017382:Reactive Oxygen Species; D001564:Benzo(a)pyrene; D006639:Histidine; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli; D004851:Epoxide Hydrolases; D010100:Oxygen