Acrylonitrile enhances H2O2-mediated DNA damage via nitrogen-centered radical formation.
Acrylonitrile (ACN) is widely used as a monomer in the polymer industry. Studies on carcinogenicity in rats exposed to ACN showed increased incidences of tumors including glial cell tumors of central nervous system and increased production of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) in glial cells. Using a high performance liquid chromatograph equipped with an electrochemical detector, we revealed that ACN enhanced the formation of 8-oxo-dG induced by H2O2 and Cu(II) whereas ACN itself did not cause DNA damage. The enhancing effect of ACN was much more efficient in the double-stranded DNA than that in the single-stranded DNA. Experiments with 32P-labeled DNA revealed that addition of ACN enhanced the site-specific DNA damage at guanines, particularly at 5'-site of the GG and GGG sequences while H2O2/Cu(II) induced piperidine-labile sites at thymine, cytosine, and guanine residues. An electron spin resonance spectroscopy using alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone showed that a nitrogen-centered radical was generated from ACN in the presence of H2O2 and Cu(II). It is considered that ACN enhances H2O2-mediated DNA damage via nitrogen-centered radical formation. We will discuss the mechanism of the enhancing effect on oxidative DNA damage in relation to expression of ACN carcinogenicity.
Murata
M
M
Department of Hygiene, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Ohnishi
S
S
Kawanishi
S
S
D000181:Acrylonitrile / Q000009:adverse effects* / Q000737:chemistry; D000818:Animals; D002273:Carcinogens / Q000009:adverse effects* / Q000737:chemistry; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000009:adverse effects*; D018736:DNA Adducts; D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy; D006147:Guanine / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000009:adverse effects* / Q000737:chemistry; D016877:Oxidants / Q000009:adverse effects* / Q000737:chemistry; D013950:Thymus Gland
D002273:Carcinogens; D018736:DNA Adducts; D016877:Oxidants; D006147:Guanine; D003300:Copper; D006861:Hydrogen Peroxide; D000181:Acrylonitrile