Drug-protein conjugates--X. The role of protein conjugation in the disposition of dinitrofluorobenzene.
The metabolism and irreversible protein binding of 2,4-[3,5-3H]dinitrofluorobenzene (3H-DNFB), a model chemically reactive compound, were studied in the rat. 3H-DNFB given intravenously (5 micrograms, 5 mg or 25 mg per kg) to anaesthetized cannulated rats was rapidly metabolized via the mercapturic acid pathway. The metabolites were extensively eliminated in bile and urine: predominantly as the glutathione conjugate and mercapturate in bile, and as the mercapturate in urine. Only ca. 3-10% of the doses remained in the liver, kidneys, spleen, heart and lungs at 3 hr. Dinitrophenyl mercapturate was the principal urinary metabolite in conscious rats dosed i.v. (5 mg or 25 mg per kg). Only 15-25% of the radiolabelled material in liver and kidney at 3 hr was irreversibly bound to protein, but 45-99% of that in the other organs and 49-88% in plasma was irreversibly bound. Preliminary evidence for the metabolism of 3H-DNFB (5 mg/kg and 25 mg/kg doses) to N2-acetyl-N6-DNP-lysine, a novel conjugate and metabolite of dinitrophenylated proteins in vivo, is presented.
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004139:Dinitrofluorobenzene / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D009578:Nitrobenzenes / Q000378:metabolism*; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats
D000596:Amino Acids; D001798:Blood Proteins; D009578:Nitrobenzenes; D011506:Proteins; D004139:Dinitrofluorobenzene