NUTRITIONAL FOLATE-DEFICIENCY AUGMENTS THE IN-VIVO MUTAGENIC AND LYMPHOCYTOTOXIC ACTIVITIES OF ALKYLATING-AGENTS

To investigate the interaction of folate deficiency and alkylating age nts in vivo, weanling Fischer 344 rats were maintained for 5 weeks on a folate replete, moderately folate deficient, or a severely Folate de ficient diet. Mutant frequencies at the HPRT locus in splenic lymphocy tes were 1.2 +/- 0.6, 1.9 +/- 1.1, and 6.4 +/- 4.0 x 10(-6), respectiv ely (P < 0.01). N-nitroso-N-ethylurea (ENU), 100 mg/kg body weight, wa s much more mutagenic with progressive folate deficiency (5.0 +/- 2.4 vs. 16.2 +/- 7.3 vs. 39.2 +/- 21.0 x 10(-6)), suggesting a synergistic interaction (P much less than 0.01). Neither moderate nor severe fola te deficiency significantly enhanced the mutagenic effects of cyclopho sphamide, 50 mg/kg body weight (18.0 +/- 7.9 vs. 6.0 +/- 2.8 vs. 28.5 +/- 28.2 x 10(-6)). The number of cloning cells/spleen were reduced 68 % in moderately folate deficient rats and by 87% in severely deficient animals (P < 0.05). The combination of folate deficiency and cyclopho sphamide reduced the total number of cloning cells further, but ENU al one, or in combination with folate deficiency, did not. These findings indicate that folate deficiency increases the risk of somatic mutatio ns and is lymphocytotoxic in rats. Folate deficiency enhances the muta genic but not the lymphotoxic effects of ENU, while it increases the l ymphotoxic but not the mutagenic activity of cyclophosphamide. Correct ion of folate deficiency may decrease the immunologic and genetic dama ge caused by some alkylating agents. Environ. Mol. Mutagen. 32.33-38, 1998 (C) 1998 Wiley-Liss, Inc.