Nutritional folate deficiency augments the in vivo mutagenic and lymphocytotoxic activities of alkylating agents.
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.
Department of Medicine, University of Vermont, Burlington 05401, USA.
R F
RF
Branda
M
M
Hacker
A
A
Lafayette
E
E
Nigels
L
L
Sullivan
J A
JA
Nicklas
J P
JP
O'Neill
D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D003520:Cyclophosphamide / Q000633:toxicity; D005038:Ethylnitrosourea / Q000633:toxicity; D005494:Folic Acid Deficiency / Q000473:pathology*; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013601:T-Lymphocytes / Q000187:drug effects*
D000477:Alkylating Agents; D009153:Mutagens; D003520:Cyclophosphamide; D007041:Hypoxanthine Phosphoribosyltransferase; D005038:Ethylnitrosourea