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Determination and metabolism of dithiol chelating agents. III. Formation of oxidized metabolites of 2,3-dimercaptopropane-1-sulfonic acid in rabbit.
Maiorino RM; Weber GL; Aposhian HV
Drug Metab Dispos 1988 May; 16(3):455-463
A study was done to detect, isolate, and determine the structures of putative oxidized disulfide metabolites of 2,3-dimercaptopropane-1- sulfonic-acid (74613) (DMPS) in urine of treated rabbits. Male New- Zealand-White-rabbits were given unlabeled or carbon-14 labeled DMPS by intramuscular injection at 0.2 millimoles per 0.3 milliliters per kilogram. Urine was collected over the next 6 hours, alkylated, and analyzed by high pressure liquid chromatography (HPLC), atomic absorption spectroscopy (AAS), and fast atom bombardment mass spectrometry (FABMS). A mean of 3.8 percent of administered DMPS was excreted unaltered in urine over 6 hours, most of it during the first 0.5 hour. Reduction with sodium-borohydride yielded 81.8 percent of DMPS in urine, with a peak between 1 and 2 hours. Analysis of zinc and copper indicated that disulfide metabolites were not chelates of these metals. HPLC analysis suggested cyclic and acyclic disulfide metabolites which were not zinc or copper chelates. These were converted to DMPS by dithiothreitol reduction. The metabolites were identified as cyclic and acyclic polymeric disulfides by FABMS. A dimer of the parent compound comprised one acyclic disulfide. Unaltered DMPS and acyclic polymeric disulfides decreased in urine over time and cyclic polymers increased, suggesting oxidation of acyclic to cyclic products. Over 6 hours, total carbon-14 in urine was represented by 5 percent unaltered DMPS, 51 percent cyclic polymeric disulfides, 33 percent acyclic polymeric disulfides, and 11 percent unknown compounds. Spontaneous in-vitro oxidation occurred at rates different from those in-vivo but produced the corresponding disulfides. The authors conclude that both spontaneous and enzymatic oxidation reduction reactions are occurring in conversion of DMPS to disulfides.
NIOSH-Publication; NIOSH-Grant; Pulmonary-system-disorders; Metabolic-study; Thiols; Laboratory-animals; In-vivo-studies; Urinalysis; Oxidation-reduction-reactions; Chromatographic-analysis; Mass-spectrometry; Atomic-absorption-spectrometry; In-vitro-studies
Molecular and Cellular Biology University of Arizona Biosciences West Bldg Tucson, AZ 85721
Issue of Publication
Drug Metabolism and Disposition
University of Arizona, Tucson, Arizona
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