Potential metabolic mutagens of caffeine and various methylxanthines

Xanthine N-carbinols, potential metabolites of caffeine and other methylxanthines, have been synthesized, characterized, and derivatized. Such intermediates, the initial metabolites arising from the cytochrome P-450 oxidation of the nitrogen-bound methyl groups, may be viewed as biological N-carbinols capable of alkylating proteins and nucleic acids. Evaluation of these compounds against Salmonella typhimurium, strain TA100, has demonstrated that, in contrast to caffeine, 7-hydroxymethyltheophylline and the 3,7-bis(hydroxymethyl)-1-methylxanthine mixture did exhibit cytotoxicity. There was no evidence of mutagenesis and it is possible that the Ames assay system is not applicable to N-carbinols.