Metabolism and pharmacokinetics of [14C]-deoxyfructosylserotonin creatinine sulfate administered orally and intravenously to rats and mice.

Deoxyfructosylserotonin (DFS) has been shown in in vitro tests to inhibit L-DOPA-oxidase and also to suppress the multiplication of Mycobacterium leprae. The possible therapeutic use of DFS makes necessary the study of its metabolic fate in animal models. Labelled [14C]-DFS was synthesized by condensation of serotonin and [14C]-glucose and administered per os or intravenously to rats and mice. After oral administration, some of the radioactivity transited through the intestinal tract to be excreted in feces (20-60% of the dose) and some was destroyed in the pH conditions of the intestine and further metabolized by the flora, producing 14CO2 in the expired air (10-40% of the dose). Radioactivity excreted in the urine amounted to 8-15% after 24 h. After intravenous administration, 60-90% of the dose had already been excreted in the urine after 8 h. Feces and CO2 accounted for 5-10% each. In the urine, for both routes of administration, beside DFS, half of the radioactivity corresponded to the glucuronide conjugate, while in the feces all the radioactivity found was unchanged DFS. Whole animal body autoradiography showed the presence of radioactivity in all the organs (1-2% of the dose) mainly resulting from the incorporation of labelled carbon from glucose and CO2. These results, obtained in healthy rats, demonstrate poor intestinal absorption of DFS (10% of the dose) and when it is absorbed, rapid urinary excretion. For its possible therapeutic use as an anti-leprosy drug in humans, derivatives with higher bioavailability must be attained.

The contribution of N-oxidation to the metabolism of the food-borne carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline in rat hepatocytes.

The metabolism of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a potent bacterial mutagen and rodent carcinogen formed in low quantities in cooked meat and fish, was studied in freshly isolated rat hepatocytes. Ten metabolites were characterized by various spectroscopic methods. Sulfamate formation was the major route of metabolism in hepatocytes of untreated rats whereas ring-hydroxylated sulfuric and glucuronic acid conjugates were major metabolites in animals pretreated with the enzyme inducers Aroclor-1254, beta-naphthoflavone, or isosafrole. The formation of a mutagenic metabolite through N-oxidation, 2-(hydroxyamino)-3,8- dimethylimidazo[4,5-f]quinoxaline (HNOH-MeIQx), was an important route of metabolism in hepatocytes of pretreated animals. Its metastable derivative, the N-hydroxy-N-glucuronide, also was detected. The nitro derivative of MeIQx, a direct-acting bacterial mutagen, was readily detoxified by glutathione transferase, forming a conjugate where the thiol group of glutathione displaced the nitro moiety. Low but detectable levels of N-acetyltransferase activity were observed for MeIQx and sulfamethazine in hepatocytes. HNOH-MeIQx and 4-(hydroxyamino)biphenyl (HNOH-ABP), a recognized human carcinogen, displayed acetyl coenzyme A dependent DNA binding in hepatic cytosol assays. Sulfamethazine decreased the DNA binding of HNOH-MeIQx in hepatocytes, suggesting a competition for acetyltransferase. However, the binding of HNOH-MeIQx to DNA in hepatocytes was independent of sulfotransferase since inhibitors of this enzyme, 2,6-dichloro-4-nitrophenol (DCNP) and pentachlorophenol (PCP), did not diminish DNA binding. In contrast, binding of HNOH-ABP to DNA was not decreased by sulfamethazine, but binding was diminished by both sulfotransferase inhibitors. From these inhibition experiments it appears that a major route of binding of HNOH-MeIQx to DNA in hepatocytes is mediated through O-acetyltransferase while a significant portion of HNOH-ABP bound to DNA is catalyzed by sulfotransferase.

Rapid and complete urinary elimination of [14C]-5-hydroxymethyl-2-furaldehyde administered orally or intravenously to rats.

5-Hydroxymethyl-2-furaldehyde (HMF), is a major product of sugar degradation found in food and solutions used in parenteral nutrition. Labeled [14C]HMF was synthesized by dehydration of [14C]fructose on ion-exchange resin and administered per os (po) and intravenously (iv) to rats. Metabolic balance of radioactivity demonstrated that HMF or its metabolites are rapidly eliminated in the urine with a recovery of 95-100% after 24 h. Literature reported, in some cases, 50% retention in the body. HMF was completely converted to two metabolites, which have been identified by nuclear magnetic resonance (NMR) and mass spectroscopy (MS) as 5-hydroxymethyl-2-furoic acid and N-(5-hydroxymethyl-2-furoyl)glycine. Administration of high doses of HMF showed a similar rapid elimination, but a proportional reduction of the amount of the glycine conjugate produced. Whole-animal-body autoradiography confirm that shortly after administration radioactive material was present in the liver but was mostly in the kidney and the bladder. The only significant difference between po and iv administration was the presence of a higher level of radioactive material in the brain of iv-treated rats.

Characterization of gamma-linolenic acid in Ribes seed.

The total lipid content of fruit seeds of the Ribes family ranges by weight from 18.3% in goose-berries (Ribes uva crispa) to 30.5% in black currants (Ribes nigrum). Isolation procedures and analytical methods (gas chromatography, mass spectrometry, high performance thin layer chromatography and stereospecific analysis) demonstrate that the oils from Ribes seeds contain up to 19% by weight of gamma-linolenic acid (gamma-LA, C18:3, n-6) in black currant oil. This last Ribes species thus constitutes one of the richest natural sources in gamma-LA yet described. These oils appear promising for critically ill patients who seem unable to convert linoleic acid into subsequent EFA fractions.