RESUMEN
Ascorbate-3-sulfate is a significant metabolite of ascorbic acid excreted in human urine. The characteristics of this compound were determined in experiments in which labeling with carbon-14 and tritium was used coupled with cochromatography with synthetic ascorbate-3-sulfate (both labeled and not labeled with sulfur-35) in a variety of solvent and absorbent systems.
Asunto(s)
Ácido Ascórbico/orina , Sulfatos/orina , Isótopos de Carbono , Cromatografía DEAE-Celulosa , Cromatografía en Papel , Cromatografía en Capa Delgada , Electroforesis , Humanos , Masculino , Isótopos de Azufre , TritioRESUMEN
The role of cAMP in the control of secretion from bovine adrenal chromaffin cells was examined using the adenylate cyclase activator, forskolin. Treatment of chromaffin cells with forskolin resulted in a rise in cAMP levels. Forskolin inhibited catecholamine release elicited by carbamylcholine or nicotine but had no effect on secretion evoked by 55 mM K+. Inhibition of carbamylcholine-stimulated release by forskolin was half-maximal at 10 microM forskolin. The inhibition by forskolin of secretion evoked by carbamylcholine was at a step distal to the rise in intracellular free calcium concentration ([Ca2+]i), since this rise was not inhibited by forskolin, which itself produced a small rise in [Ca2+]i. The results suggest that secretion evoked by carbamylcholine is due to the activation of an additional second messenger pathway acting with the rise in [Ca2+]i. This additional pathway may be the target for cAMP action.
Asunto(s)
Médula Suprarrenal/metabolismo , Carbacol/farmacología , Catecolaminas/metabolismo , Gránulos Cromafines/fisiología , Sistema Cromafín/fisiología , AMP Cíclico/fisiología , Potasio/farmacología , Médula Suprarrenal/efectos de los fármacos , Animales , Bovinos , Cinética , Nicotina/farmacologíaRESUMEN
Danish mice (Mus musculus domesticus) genetically resistant to the anticoagulant action of two 4-hydroxycoumarins, warfarin and bromadiolone, were examined to determine their mechanism of resistance. The hepatic vitamin K epoxide reductase in the bromadiolone-resistant mice and in one phenotype of warfarin-resistant mice was highly insensitive to in vitro inhibition by warfarin and bromadiolone. The kinetic constants for the epoxide reductase from bromadiolone-resistant mice were also altered. The Vmax for this enzyme was decreased by 40%, and the Km for the reaction reductant, dithiothreitol, was 70% lower than that of normal mice. This phenotype of Danish resistant mice appears to have a resistance mechanism that is similar to that reported for a Welsh strain of warfarin-resistant rats. The other phenotype of Danish resistant mice had a hepatic epoxide reductase that was only slightly less sensitive to warfarin inhibition than normal. The mechanism of warfarin resistance in these mice is not apparent from the available data.
Asunto(s)
4-Hidroxicumarinas/farmacología , Resistencia a Medicamentos/genética , Ratones/genética , Rodenticidas/farmacología , Warfarina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Cinética , Hígado/enzimología , Oxigenasas de Función Mixta/antagonistas & inhibidores , Oxigenasas de Función Mixta/metabolismo , Fenotipo , Vitamina K Epóxido ReductasasRESUMEN
Man does not catabolize ascorbate to CO2, whereas the monkey does catabolize ascorbate and ascorbate sulfate to CO2 when these compounds are given orally. However, it takes the same length of time to produce frank scurvy in both man and the monkey, thus indicating that the comparative storage, rate of use, and mode of metabolism of ascorbate is similar in both species. Preliminary feeding and isotope studies conducted on monkeys are in agreement with the fact that only a small amount of labeled ascorbate or ascorbate sulfate equilibrated with body stores. These results are in agreement with published ascorbic acid requirements of 10 mg/kg body weight. In our experiments, 250 mg/day had to be fed to a 10-kg monkey to completely clear all signs of scurvy and return blood ascorbate levels to normal. Ascorbic acid administered intravenously to monkeys appears to equilibrate completely with the ascorbate pool(s). Ascorbate sulfate was found to be a urinary metabolite of both ascorbic-1-14C acid and ascorbic-6-14C acid fed orally to monkeys.