Studies on the mode of action of 5-fluorocytosine in Aspergillus species.
The mode of action of 5-fluorocytosine (5-FC) was studied in three isolates of pathogenic Aspergillus with varying degrees of susceptibility to the drug. Distribution studies showed that susceptibility or resistance to 5-FC was not dependent on uptake of the drug. While only a small percentage of the total 5-FC taken up was found in the RNA fraction of the cells, most remained in the acid-soluble intracellular pool. 5-FC, 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine monophosphate (5-Fd-UMP) were among metabolites identified in the pool. In addition, fluoroorotic acid appeared to be a major constituent of the metabolites derived from 5-FC. The aspergilli also were capable of utilizing cytosine as a nitrogen source and this is suggested as a possible mechanism of resistance. A dual mode of action for 5-FC in the aspergilli is proposed. This consists of, first, incorporation of 5-FU into RNA and, second, inhibition of DNA synthesis by production of 5-FdUMP.
D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D001234:Aspergillus niger / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D002855:Chromatography, Thin Layer; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004352:Drug Resistance, Microbial; D005467:Floxuridine / Q000378:metabolism; D005437:Flucytosine / Q000378:metabolism / Q000494:pharmacology*; D005472:Fluorouracil / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008828:Microbiological Techniques; D012313:RNA / Q000378:metabolism
D005467:Floxuridine; D012313:RNA; D003596:Cytosine; D004247:DNA; D005437:Flucytosine; D005472:Fluorouracil