Role of plasma albumin in renal elimination of a mercapturic acid

Abstract

Biosynthesis of N-acetylcysteine S-conjugates of xenobiotics (mercapturic acids) occurs via interorgan metabolism and the renal transtubular transport system plays an important role in elimination of the final metabolites from the organism. To assess the behavior of a mercapturic acid in the circulation, plasma clearance of radioactive S-benzyl-N-acetylcysteine and its interaction with plasma proteins were studied in normal and mutant analbuminemic rats (NAR). Intravenously injected S-benzyl-N-acetylcysteine rapidly disappeared from the circulation both in NAR and normal animals. However, its plasma clearance was significantly higher in NAR (45.7 ml kg-' min-') than in normal rats (25.2 ml kg-' min-'). Ultrafiltration analysis revealed that 18.4% and 80.1 Yo of the mercapturate bound to plasma protein(s) from NAR and normal rats, respectively, at 50 pM ligand concentration. The mercapturic acid bound to plasma albumin with an association constant of 2.24 x lo5 M -' and the number of binding sites was 1.18/mol albumin. The binding was competitively inhibited by probenecid and L-tryptophan. Concomitant administration of this mercapturic acid with equimolar amounts of albumin resulted in a marked decrease in the plasma clearance (26.2ml kg-' min-') and an increase in the urinary secretion of this ligand in NAR. 30 min after injection of the mercapturic acid (10 pmol/kg body weight), 27.3% and 60.4% of the injected dose was recovered from urine and kidneys of NAR and normal rats respectively. About 41 YO of the dose was recovered in NAR urine when the ligand was injected bound to an equimolar amount of albumin. These results suggested that albumin is important for the renal accumulation and urinary elimination of the circulating mercapturic acid.Mercapturic acids are the final metabolites derived from glutathione S-conjugates of xenobiotics. Enzymes and transport systems involved in mercapturic acid biosynthesis are localized in different subcellular compartments of different organs, such as liver, small intestine and kidney [l -21. Previous studies [3 -61 have shown that formation and elimination of a mercapturic acid proceed under cooperative action of these organs. The acetylation of a cysteine S-conjugate, a final step of mercapturic acid biosynthesis, is important for the subsequent elimination of an N-acetyl metabolite [6]. Previous studies have revealed that an intravenously administered mercapturic acid was excreted in urine via the renal transtubular transport system for organic anions [7]. It has been well documented that most of nephrophilic organic anions, which undergo transtubular secretion, bind to plasma albumin [8, 91. Preliminary experiments in vitro have revealed that S-benzyl-N-acetylcysteine binds to albumin. This finding provided the first hint that binding of this detoxified metabolite to the circulating albumin in vivo might be important in directing the bound ligand to the kidney, where a peritubular secretory system is operating. Recent studies [lo-121 reported that amphipathic organic an...

Pharmacokinetics and Pharmacodynamics of Intravenous Azosemide in Mutant Nagase Analbuminemic Rats

“…Plasma protein binding of mercapturic acid in control rats and NARs was 80.1 and 18.4%, respectively, and the percentage of an i.v. dose excreted in 20-min urine as unchanged mercapturic acid was 57.6 and 25.6% for control rats and NARs, respectively (Okajima et al, 1985).…”

“…The importance of plasma protein binding of phenolsulfonphthalein and mercapturic acid (Okajima et al, 1985) for their urinary excretion has also been reported. The serum protein binding of phenolsulfonphthalein in control rats and NARs was 84.2 to 94.4 and 12.5 to 32.0%, respectively, and the percentage of an i.v.…”

Directing Role of Organic Anion Transporters in the Excretion of Mercapturic Acids of Alkylated Polycyclic Aromatic Hydrocarbons

“…The secretion process may be critical for the clearance of mercapturic acids, because they bind to albumin and thus cannot be efficiently filtrated (Okajima et al, 1985). Pombrio et al (2001) investigated transmembrane transport of mercapturic acids in Xenopus oocytes expressing rat OAT1.…”

Mechanism of renal peritubular extraction of plasma glutathione

“…As reflected by the ratio of the respective V,,,/Km values (Table 4), the enzymic cleavage of extravesicular GSH on the intact membrane surface might be about 26000 times more efficient than the uptake of intact GSH even when the transport system is optimized for uptake. This suggests that the enzymic degradation of peritubular GSH might occur much faster than the a These values were obtained from [33].…”

“…Values in parenthesis show the percentage of dose found in tissues. The total weight of the muscle for 100 g rat was assumed to be 43 g [33] Tissues Radioactivity observations described for Table 2, in which significant amounts of the injected GSH appeared in urine in acivicintreated animals but not in control and BSO-treated rats. Radioactivity found in other tissues, such as heart, lung and spleen, was very low.…”