Comparative Inhibiting Effects of Methylxanthines on Urethan-induced Tumors, Malformations, and Presumed Somatic Mutations in Mice1

The inhibiting effects of methylxanthines on urethan-induced lung tumors, malformations, and presumed somatic mutations in mice were studied to determine the contribution of mutational and physiological changes to chemically induced neoplasia and malformation. When young adult or pregnant ICR/Jc1 mice were treated with urethan and then methylxanthines were given, caffeine (1,3,7-trimethylxanthine) and theobromine (3,7dimethylxanthine) greatly suppressed urethan-induced tumorigenesis and teratogenesis, while theophylline (1,3-dimethylxanthine) did not. Of the three monomethylxanthines (meth ylated at positions 1, 3, or 7), 7-methylxanthine was most effective for inhibiting tumors and malformations, indicating that the methyl group at position 7 is most active. Contribution of cyclic adenosine 3':5'-monophosphate was ruled out, since urethan-induced tumorigenesis and teratogenesis were not affected by theophylline which elevates the cellular level of cyclic adenosine 3':5'-monophosphate by inhibiting phosphodiesterase more effectively than caffeine does; instead, tumor igenesis and teratogenesis were greatly inhibited by theobro mine and 7-methylxanthine, which do not alter the level of cyclic adenosine 3':5'-monophosphate. To test the mutational origin of cancer and malformation, the effects of caffeine on urethan induction of somatic mutations in PT X HT F-, mice were examined, because caffeine is known to inhibit ultravioietand 4-nitroquinoline 1-oxide-initiated mutagenesis in Escherich/a coli by inhibiting error-prone repair. In mice, however, caffeine did not inhibit urethan-induced somatic mutations. Furthermore, theophylline, an inhibitor of error-pror.e repair, did not reduce the yields of tumors and malformations. Antineoplastic and antiteratogenic effects of caffeine may be caused not by the inhibition of the mutational change but by the inhibition of the subsequent process for expressing tumors and malformations.