Influence of dietary carrot on cytostatic drug activity of cyclophosphamide and its main directly acting metabolite: induction of sister-chromatid exchanges in normal human lymphocytes, Chinese hamster ovary cells, and their DNA repair-deficient cell lines.
We have utilized an in vivo drug metabolism technique (i.e. injecting the chemical into rat and isolating plasma with metabolites from blood) for detecting the genotoxicity of indirectly acting cyclophosphamide and its directly acting metabolite phosphoramide mustard in cultures of human peripheral blood lymphocytes of normal individuals, Fanconi's anaemia (FA) and aplastic anaemia (AA) patients, wild-type Chinese hamster ovary cells (CHO) and its DNA repair-deficient mutant 43-3B cells. In addition, the influence of dietary carrot on the clastogenic activity of these 2 chemicals in all the different cell types was studied. The genotoxicity was assessed by the ability of the metabolites of these agents to induce sister-chromatid exchanges in the treated cells. A dose-dependent increase in the frequencies of sister-chromatid exchanges was observed in all cell strains following treatment with activated metabolites of cyclophosphamide or phosphoramide mustard. The sensitivity of lymphocytes from normal donors, FA and AA patients to these 2 chemicals was similar. In CHO cell lines the induced frequency of sister-chromatid exchanges was slightly higher after treatment with the metabolites of cyclophosphamide than with phosphoramide mustard. The mutant 43-3B cells responded with higher frequencies of SCEs when compared to the wild-type CHO cells, about 1.5-2-fold, at low doses. Pretreating of rats with fresh carrot juice effectively inhibited the increase in the frequencies of sister-chromatid exchanges induced by cyclophosphamide in wild-type and mutant CHO cells (P less than 0.01), and to a lesser extent in human lymphocytes (p less than 0.05). In contrast, no inhibitory effect was observed in any of these cell types in combination of dietary carrot for direct acting phosphoramide mustard on the frequency of induced sister-chromatid exchanges. The possibility that dietary carrot exerts its antimutagenic effect by affecting the processes of enzymatic activation of cyclophosphamide is discussed.
Darroudi
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Department of Radiation Genetics and Chemical Mutagenesis, State University of Leiden, Sylvius Laboratories, The Netherlands.
Targa
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Natarajan
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D000741:Anemia, Aplastic / Q000235:genetics / Q000473:pathology; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D003520:Cyclophosphamide / Q000378:metabolism / Q000494:pharmacology*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005199:Fanconi Anemia / Q000235:genetics / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000648:ultrastructure; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D010053:Ovary; D010752:Phosphoramide Mustards / Q000494:pharmacology*; D051381:Rats; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D014675:Vegetables
D010752:Phosphoramide Mustards; C030090:phosphoramide mustard; D003520:Cyclophosphamide