N6-adenyl arylation of DNA by aristolochic acid II and a synthetic model for the putative proximate carcinogen.
Aristolochic acid II (AAII), one of the major components of the carcinogenic plant extract aristolochic acid, is known to be mutagenic and to form DNA adducts in vitro and in vivo. The major fluorescent DNA adduct formed upon xanthine oxidase mediated reduction in the presence of calf thymus (CT-) DNA or deoxyadenosine was isolated by means of preparative HPLC and identified by fluorescence, UV/vis absorbance, and 1H NMR spectroscopy as 7-(deoxy-adenosin-N6-yl)aristolactam II. As a model proximate carcinogen, N-chloroaristolactam II was prepared chemically from aristolactam II, the reduction product of AAII. This model compound was spectroscopically characterized and found to react directly with CT-DNA without any activation, forming the same deoxyadenosine adduct. HPLC analysis with fluorescence monitoring detected this adduct in vivo in the liver DNA of Wistar rats treated orally with AAII. These results confirm the anticipated metabolic activation mechanism of AAII as occurring via a cyclic nitrenium ion.
Pfau
W
W
German Cancer Research Center, Institute of Toxicology and Chemotherapy, Heidelberg.
Schmeiser
H H
HH
Wiessler
M
M
D000225:Adenine / Q000737:chemistry*; D000470:Alkaloids / Q000737:chemistry; D000818:Animals; D034341:Aristolochic Acids; D002273:Carcinogens / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry*; D003839:Deoxyadenosines / Q000737:chemistry; D004789:Enzyme Activation; D005456:Fluorescent Dyes; D005960:Glucosides / Q000737:chemistry; D006997:Hypochlorous Acid / Q000737:chemistry; D066298:In Vitro Techniques; D008099:Liver / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000737:chemistry*; D051381:Rats; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D014969:Xanthine Oxidase / Q000378:metabolism
D000470:Alkaloids; D034341:Aristolochic Acids; D002273:Carcinogens; D003839:Deoxyadenosines; D005456:Fluorescent Dyes; D005960:Glucosides; D010616:Phenanthrenes; C062008:aristololactam-glucoside; D006997:Hypochlorous Acid; D004247:DNA; C042310:aristolochic acid II; D014969:Xanthine Oxidase; D000225:Adenine