ASCORBIC-ACID (VITAMIN-C) MODULATES THE MUTAGENIC EFFECTS PRODUCED BYAN ALKYLATING AGENT IN-VIVO

Recent reports suggest that ascorbic acid (vitamin C) inhibits tumorig enesis as well as exerts a protective effect against mutagenesis in vi tro; however, there is no information on its ability to affect gene mu tations induced in vivo. In this study, we have investigated the antim utagenic effects of ascorbic acid on the frequency of 6-thioguanine-re sistant (6-TG(r)) T-lymphocytes produced in Fischer 344 rats dosed wit h the direct-acting alkylating agent, N-ethyl-N-nitrosourea (ENU). The frequency of 6-TG(r) T-lymphocytes from the spleen measured five week s after ENU treatment indicated that ENU produced a substantial mutage nic response. Pretreatment and/or post-treatment of mts with ascorbic acid administered in the drinking water appeared to inhibit the respon se, but the inhibition was statistically significant only when data fr om the various dosing schedules were pooled. In addition, there was no clear dose-dependency to the inhibitory effect of ascorbic acid. To f urther evaluate the time effects of the vitamin supplement on ENU muta genicity, rats were exposed to the mutagen together with ascorbic acid , which was given continuously for the entire duration of the experime nt. At specific times after ENU treatment, the frequency of 6-TG(r) T- cells was determined in lymphocytes isolated from the spleen and the t hymus. Time-dependent increases in the frequency of 6-TG(r) T-cells we re observed with ENU treatment; ascorbic acid significantly reduced th e ENU-mediated mutagenic responses, most dramatically in the spleen at weeks 6 and 8 (P < 0.0001), and to a lesser extent in the thymus (P < 0.01 at week 6 and P < 0.006 at week 8). Our data suggest that ascorb ic acid intake affects the in vivo mutagenicity of ENU, a direct-actin g mutagen/carcinogen, and that the reported inhibitory effects of the antioxidant on carcinogenesis may be partially mediated by its effects on mutagenesis. Although it is difficult to extrapolate from rodent s tudies to humans, the results presented suggest an explanation for epi demiological data that link vitamin C ingestion with decreased cancer risk. (C) 1994 Wiley-Liss, Inc.