Oxidative DNA damage induced by benz[a]anthracene metabolites via redox cycles of quinone and unique non-quinone.
Benz[a]anthracene (BA) is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) that are ubiquitous environmental pollutants. PAH carcinogenesis is explained by DNA adduct formation by PAH diol epoxide and oxidative DNA damage by PAH o-quinone. Benz[a]anthracene-trans-3,4-dihydrodiol (BA-3,4-dihydrodiol) is a minor metabolite but shows higher mutagenicity and tumorigenicity than parent BA. We confirmed that a BA o-quinone type metabolite, benz[a]anthracene-3,4-dione (BA-3,4-dione), induced oxidative DNA damage in the presence of cytochrome P450 reductase. Interestingly, we found that BA-3,4-dihydrodiol nonenzymatically caused Cu(II)-mediated DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine formation and the addition of NADH enhanced DNA damage. BA-3,4-dihydrodiol induced a double-base lesion of C and G at the 5'-ACG-3' sequence complementary to codon 273 of the human p53 tumor suppressor gene, which is known as a hotspot. The DNA damage was inhibited by catalase and bathocuproine, indicating the involvement of H(2)O(2) and Cu(I). Time-of-flight mass spectroscopic study suggested that BA-3,4-dihydrodiol undergoes Cu(II)-mediated autoxidation leading to the formation of its hydroxylated form of BA-3,4-dihydrodiol, capable of causing oxidative DNA damage. It is noteworthy that BA-3,4-dihydrodiol can nonenzymatically induce DNA damage more efficiently than BA-3,4-dione with metabolic activation. In conclusion, oxidative DNA damage induced by BA-3,4-dihydrodiol not only via quinone-type redox cycle but also via a new type of redox cycle participates in the expression of carcinogenicity of BA and BA-3,4-dihydrodiol.
Seike
Kazuharu
K
Department of Environmental and Molecular Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Murata
Mariko
M
Oikawa
Shinji
S
Hiraku
Yusuke
Y
Hirakawa
Kazutaka
K
Kawanishi
Shosuke
S
D000818:Animals; D001551:Benz(a)Anthracenes / Q000009:adverse effects* / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D003300:Copper / Q000378:metabolism / Q000494:pharmacology; D004249:DNA Damage / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D003839:Deoxyadenosines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D019942:Genes, p16 / Q000187:drug effects; D011905:Genes, ras / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D006801:Humans; D009243:NAD / Q000378:metabolism / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010618:Phenanthrolines / Q000494:pharmacology; D010761:Phosphorus Radioisotopes; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects; D011809:Quinones / Q000009:adverse effects* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects
D001551:Benz(a)Anthracenes; D003839:Deoxyadenosines; D010618:Phenanthrolines; D010761:Phosphorus Radioisotopes; D011084:Polycyclic Aromatic Hydrocarbons; D011809:Quinones; D016159:Tumor Suppressor Protein p53; C495788:benz(a)anthracene-3,4-dihydrodiol; C495787:benz(a)anthracene-3,4-dione; D009243:NAD; C024829:8-hydroxyguanine; D006147:Guanine; C021624:benzanthracene-1,2-dihydrodiol; C078251:2'-deoxy-7,8-dihydro-8-oxoadenosine; D003300:Copper; C002478:bathocuproine; D002374:Catalase; D009251:NADPH-Ferrihemoprotein Reductase; C029892:cupric chloride