Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora
5-Fluorocytosine (FC) is used to treat systemic fungal infections in man. Its clinical effectiveness has been limited by hematologic toxicity which may be secondary to the formation of 5-fluorouracil (FU). It is unclear how FU is formed since human cells lack cytosine deaminase. The present study examined if intestinal microflora (IMF) could convert FC to FU in man. An in vitro semicontinuous culture system was inoculated with human feces and maintained with sterile nutrient suspension. The microbial community was assessed for cell count and anaerobes as well as formation of volatile fatty acids and CH/sub 4/. The system approximated that believed to occur in vivo. The study was initiated with addition of purified (6-/sup 14/C)-FC. Unlabelled FC was then added to the system daily for 2 weeks following which (6-/sup 14/C)-FC was again added. Following each addition of (6-/sup 14/C)-FC, samples were removed at 2,4,8,24,48,72, and 96 hr. Utilizing HPLC, FC and FU could be separated with quantitation of radioactivity in each peak. Following the initial dose, no detectable FU was observed during the first 8 hr, but after 24 hr increasing levels were detected (9.42 ..mu..g FU/ml after 4 days). Following chronic administration of FC, increased levles of FU were noted without an 8 hr lag time in the production of FU (31.86 ..mu..g FU/ml after 4 days). In summary, these studies demonstrate that IMF can convert FC to FU possibly accounting for toxicity observed following administration of FC.
- Research Organization:
- Univ. of Alabama, Birmingham
- OSTI ID:
- 5316971
- Report Number(s):
- CONF-8604222-; TRN: 86-028574
- Journal Information:
- Fed. Proc., Fed. Am. Soc. Exp. Biol.; (United States), Vol. 45:3; Conference: 70. annual meeting of the Federation of American Society for Experimental Biology, St. Louis, MO, USA, 13 Apr 1986
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
CYTOSINE
METABOLISM
FLUOROURACILS
TOXICITY
CARBON 14 COMPOUNDS
FECES
INTESTINES
LIQUID COLUMN CHROMATOGRAPHY
MAN
MICROORGANISMS
TRACER TECHNIQUES
AMINES
ANIMALS
ANTIMETABOLITES
AZINES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BODY
CHROMATOGRAPHY
DIGESTIVE SYSTEM
DRUGS
GASTROINTESTINAL TRACT
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
ISOTOPE APPLICATIONS
LABELLED COMPOUNDS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
ORGANIC FLUORINE COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
PRIMATES
PYRIMIDINES
SEPARATION PROCESSES
URACILS
VERTEBRATES
WASTES
560302* - Chemicals Metabolism & Toxicology- Microorganisms- (-1987)
550501 - Metabolism- Tracer Techniques