Modifications of deoxycytidine kinase and deaminase activities by docosahexaenoic acid in normal and transformed rat fibroblasts.
Deoxycytidine kinase (dCK) and deoxycytidine deaminase (dCDA) are two key enzymes in the activation and inactivation, respectively, of deoxycytidine (dCyd) and several chemotherapeutically important nucleoside analogues. To investigate whether supplementation of docosahexaenoic acid, an n-3 fatty acid found mainly in fish oil, can modulate the activity of both enzymes, normal (Rat-2) and transformed (NW-16) rat fibroblasts were cultured in medium supplemented with or without DHA. DHA supplementation increased the phosphorylation efficiency (V(max)/K(m)) of dCK but decreased the deamination efficacy of dCDA in the transformed cells as compared with those in the normal fibroblasts. Enzyme activity of dCK was decreased by DHA in Rat-2 cells and increased in NW-16 cells. In contrast, dCDA activity was elevated in the normal fibroblasts in response to DHA. As a result, the activity ratio of dCK/dCDA (a potential indicator of chemosensitivity) was decreased in the normal fibroblasts but increased in the transformed cells by DHA. We have observed previously that the toxicity of nucleoside drugs (particularly arabinosylcytosine) was increased in tumor cells and decreased in normal cells in response to DHA and proposed a mechanism of changes in drug activation/inactivation. The present data support this hypothesis and suggest that DHA has the potential to selectively target chemotherapeutic drugs toward tumor cells while at the same time reducing host toxicity.
Cha
Ming C
MC
Department of Human Biology and Nutrition Sciences, University of Guelph, Animal Science and Nutrition Building, Ont., N1G 2W1, Guelph, Canada.
Meckling-Gill
Kelly A
KA
D000704:Analysis of Variance; D000818:Animals; D002471:Cell Transformation, Neoplastic; D003844:DCMP Deaminase / Q000378:metabolism*; D003841:Deoxycytidine / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology; D051381:Rats
D003841:Deoxycytidine; D004281:Docosahexaenoic Acids; D003842:Deoxycytidine Kinase; D003844:DCMP Deaminase