Acetaminophen Nephrotoxicity in the CD-1 Mouse. II. Protection by Probenecid and AT-125 without Diminution of Renal Covalent Binding

Sg, Emeigh Hart; Ds, Wyand; Ea, Khairallah; Sd, Cohen

doi:10.1006/taap.1996.0020

Cited by 32 publications

(4 citation statements)

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“…However, with buthionine sulfoximine pretreatment, this challenge dose of acetaminophen caused liver and kidney injury as evidenced by elevated plasma sorbitol dehydrogenase activity and BUN content at 12 hr. The plasma blood urea nitrogen elevation was similar to that observed after 600 mg acetaminophen/kg without buthionine sulfoximine co‐treatment (Emeigh Hart et al 1994 & 1996). By contrast, plasma sorbitol dehydrogenase activity after 125 mg acetaminophen/kg while significantly above control and indicative of injury was much lower than the activity usually observed after the normally toxic 600 mg/kg dose (Placke et al 1987a).…”

Section: Discussionsupporting

confidence: 76%

Effect of Ribose Cysteine Pretreatment on Hepatic and Renal Acetaminophen Metabolite Formation and Glutathione Depletion

Slitt

Dominick

Roberts

et al. 2005

Basic Clin Pharma Tox

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Ribose cysteine (2(R,S)-D-ribo-(1ø,2ø,3ø,4ø-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid) protects against acetaminophen-induced hepatic and renal toxicity. The mechanism for this protection is not known, but may involve inactivation of the toxic electrophile via enhancement of glutathione (GSH) biosynthesis. Therefore, the goal of this study was to determine if GSH biosynthesis was required for the ribose cysteine protection. Male CD-1 mice were injected with either acetaminophen or acetaminophen and ribose cysteine. The ribose cysteine cotreatment antagonized the acetaminophen-induced depletion of non-protein sulfhydryls in liver as well as GSH in kidney. Moreover, ribose cysteine cotreatment significantly increased the concentration of acetaminophen-cysteine, hepatic acetaminophen-mercapturate in liver and renal acetaminophen-GSH metabolites in kidney 4 hr after acetaminophen. To determine whether protection against acetaminophen-induced liver and kidney damage involved ribose cysteine dependent GSH biosynthesis, buthionine sulfoximine was used to selectively block g-glutamylcysteine synthetase (g-GCS). Plasma sorbitol dehydrogenase (SDH) activity and blood urea nitrogen from mice pretreated with buthionine sulfoximine and challenged with acetaminophen indicated that both liver and kidney injury had occurred. While co-treatment with ribose cysteine had previously protected against acetaminophen-induced liver and kidney injury, it did not diminish the acetaminophen-induced damage to either organ in the buthionine sulfoximine-treated mice. In conclusion, ribose cysteine serves as a cysteine prodrug that facilitates GSH biosynthesis and protects against acetaminophen-induced target organ toxicity.

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Section: Discussionsupporting

confidence: 76%

Effect of Ribose Cysteine Pretreatment on Hepatic and Renal Acetaminophen Metabolite Formation and Glutathione Depletion

Slitt

Dominick

Roberts

et al. 2005

Basic Clin Pharma Tox

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“…Furthermore, according to the Chinese Pharmacopoeia 2000, normal human dose in clinical prescription for Aristolochia manschuriensis is 60 g/day/person; while the average content of AAI in it was reported to be 2610 μg/g, the clinical exposure could be as high as 3.132 mg/kg/day (50 kg/person) when not considering the loss during the formulation preparation, so our doses are relevant to clinic. (2) The PRB + AAI group mice were ip injected with PRB at 150 mg/kg in 10 mL/kg isotonic saline, 30 min before the administration of AAI; this dosing regimen for PRB has been shown to inhibit organic anion transport . The kidney, liver and serum levels of PRB at 15–120 min after AAI treatment in this experiment were determined to be 0.19–0.68 mM, 0.19–1 mM and 0.14–1.72 mM, respectively; the plasma protein unbound fraction of PRB is determined to be 0.77 ± 0.01 so the PRB concentration in vivo was high enough to inhibit the activity of OATs.…”

Section: Methodsmentioning

confidence: 99%

Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I

et al. 2011

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Ingestion of aristolochic acid (AA), especially its major constituent aristolochic acid I (AAI), results in severe kidney injury known as aristolochic acid nephropathy (AAN). Although hepatic cytochrome P450s metabolize AAI to reduce its kidney toxicity in mice, the mechanism by which AAI is uptaken by renal cells to induce renal toxicity is largely unknown. In this study, we found that organic anion transporters (OATs) 1 and 3, proteins known to transport drugs from the blood into the tubular epithelium, are responsible for the transportation of AAI into renal tubular cells and the subsequent nephrotoxicity. AAI uptake in HEK 293 cells stably transfected with human OAT1 or OAT3 was greatly increased compared to that in the control cells, and this uptake was dependent on the AAI concentration. Administration of probenecid, a well-known OAT inhibitor, to the mice reduced AAI renal accumulation and its urinary excretion and protected mice from AAI-induced acute tubular necrosis. Further, AAI renal accumulation and severe kidney lesions induced by AAl in Oat1 and Oat3 gene knockout mice all were markedly suppressed compared to those in the wild-type mice. Together, our results suggest that OAT1 and OAT3 have a critical role in AAl renal accumulation and toxicity. These transporters may serve as a potential therapeutic target against AAN.

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“…Acetaminophen has raised great concern because it is the main metabolite of phenacetin. It has been shown to induce apoptosis in murine proximal tubular epithelial cells3 and lead to acute renal injury in human and experimental animals 4, 5. Conventional NSAIDs inhibit the cyclooxygenase activity and their short‐term adverse renal effects, including sodium retention, elevation of blood pressure, and acute renal failure, have been well documented 6, 7.…”

Section: Introductionmentioning

confidence: 99%

Analgesic use and the risk for progression of chronic kidney disease

Kuo

Tsai

Tiao

et al. 2010

Pharmacoepidemiology and Drug

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Acetaminophen Nephrotoxicity in the CD-1 Mouse. II. Protection by Probenecid and AT-125 without Diminution of Renal Covalent Binding

Cited by 32 publications

References 0 publications

Effect of Ribose Cysteine Pretreatment on Hepatic and Renal Acetaminophen Metabolite Formation and Glutathione Depletion

Effect of Ribose Cysteine Pretreatment on Hepatic and Renal Acetaminophen Metabolite Formation and Glutathione Depletion

Critical Role of Organic Anion Transporters 1 and 3 in Kidney Accumulation and Toxicity of Aristolochic Acid I

Analgesic use and the risk for progression of chronic kidney disease

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