The metabolic activation of the carcinogen 1'-hydroxysafrole in vivo and in vitro and the electrophilic reactivities of possible ultimate carcinogens.
Administration of [2',3'-3H]-1'-hydroxysafrole to rats or mice resulted in the formation of hepatic DNA-, ribosomal RNA-, and protein-bound 3H derivatives. Alkaline digestion of the 3H-protein released 0.1 to 0.3% of the 3H as a derivative that was identified as 3'-methylmercaptoisosafrole by its cochromatography in five solvent systems with the synthetic compound. 1'-Hydroxysafrole was metabolized at a low rate by rat and mouse liver cytosols in a 3'-phosphoadenosine 5'-phosphosulfate-dependent reaction to a derivative (presumably the sulfuric acid ester) that was captured by its reaction with RNA. Likewise, 1'-hydroxysafrole was oxidized at a low rate by rat and mouse liver microsomes to 1'-hydroxysafrole-2',3'-oxide in a reduced nicotinamide adenine dinucleotide phosphate-dependent reaction. Both of these electrophilic metabolites are candidate ultimate carcinogenic derivatives of 1'-hydroxysafrole. The electrophilic reactivities of various safrole derivatives with nucleosides were determined to be in the order of 1'-oxosafrole greater than 1'-acetoxysafrole greater than 1'-acetoxysafrole-2',3'-oxide greater than 1'-hydroxysafrole-2',3'-oxide greater than safrole-2',3'-oxide greater than or equal to 1'-oxosafrole-2',3'-oxide. The major reactions were generally observed with guanosine. A major reaction product of 1'-acetoxysafrole and guanosine 5'-monophosphate yielded 3'-hydroxyisosafrole under very mild acidic conditions. These data further substantiate the previous characterization of this reaction product as O-6-(isosafrol-3'-yl)guanylic acid. The syntheses of 1'-oxosafrole, 2',3'-dehydrosafrole, [2',3'-3H]-1'-hydroxysafrole, and the 2',3'-oxed.
D000123:Acetyltransferases / Q000032:analysis; D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004149:Dioxoles / Q000378:metabolism*; D006151:Guanosine / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D009705:Nucleosides / Q000378:metabolism; D010084:Oxidation-Reduction; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D051381:Rats; D012451:Safrole / Q000031:analogs & derivatives / Q000378:metabolism*; D013466:Sulfurtransferases / Q000032:analysis
D002273:Carcinogens; D004149:Dioxoles; D009705:Nucleosides; D011506:Proteins; D012335:RNA, Ribosomal; D006151:Guanosine; C012434:3'-methylmercaptoisosafrole; D010724:Phosphoadenosine Phosphosulfate; D009249:NADP; D004247:DNA; C012376:1'-hydroxysafrole; D000123:Acetyltransferases; D013466:Sulfurtransferases; D012451:Safrole