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 > 1′-acetoxysafrole > 1′-acetoxysafrole-2′,3′-oxide > 1′-hydroxysafrole-2′,3′-oxide > safrole-2′,3′-oxide ≥ 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′-oxides of 1′-hydroxysafrole, 1-oxosafrole, and 1′-acetoxysafrole are described.
This work was supported by Grants CA-07175, CA-15785, and CRTY-5002 of the National Cancer Institute, USPHS.