To investigate the interaction of
folate deficiency and
alkylating agents in vivo, weanling Fischer 344 rats were maintained for 5 weeks on a
folate replete, moderately
folate deficient, or a severely
folate deficient diet. Mutant frequencies at the
HPRT locus in splenic lymphocytes were 1.2+/-0.6, 1.9+/-1.1, and 6.4+/-4.0 x 10(-6), respectively (P < 0.01). N-nitroso-
N-ethylurea (ENU), 100 mg/kg
body weight, was 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 << 0.01). Neither moderate nor severe
folate deficiency significantly enhanced the mutagenic effects of
cyclophosphamide, 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
cyclophosphamide reduced the total number of cloning cells further, but ENU alone, or in combination with
folate deficiency, did not. These findings indicate that
folate deficiency increases the risk of somatic mutations and is lymphocytotoxic in rats.
Folate deficiency enhances the mutagenic but not the lymphotoxic effects of ENU, while it increases the lymphotoxic but not the mutagenic activity of
cyclophosphamide. Correction of
folate deficiency may decrease the immunologic and genetic damage caused by some
alkylating agents.