TY - JOUR
T1 - Nephrotoxicity of 2-bromo-(cystein-s-yl) hydroquinone and 2-bromo-(N-acetyl-l-cystein-S-yl) hydroquinone thioethers
AU - Monks, Terrence J.
AU - Jones, Thomas W.
AU - Hill, Barbara A.
AU - Lau, Serrine S.
N1 - Funding Information:
’ Preliminary accounts of this work were presented at the Society of Toxicology annual meetings in Miami Beach, FL. February 1990 and Dallas, TX, February 1991. * This work was supported in part by United States Public Health Service Awards ES 04662 (T.J.M.). ES 05436 (T.W.J.), and GM 39338 (S.S.L.). ’ Recipient of a P.M.A. Foundation lowship. 4 Recipient of a P.M.A. Foundation ment Award.
PY - 1991/11
Y1 - 1991/11
N2 - The in vivo toxicity of isomeric cystein-S-yl and N-acetylcystein-S-yl conjugates of 2-bromohydroquinone was determined in male Sprague-Dawley rats. 2-Bromo-(dicystein-S-yl)hydroquinone [2-Br-(diCYS)HQ] and 2-bromo-(di-N-acetyl-l-cystein-S-yl)hydroquinone [2-Br-(diNAC)HQ] were considerably more nephrotoxic than their corresponding monosubstituted thioethers and 2-Br-(diCYS)HQ was more nephrotoxic than 2-Br-(diNAC)HQ. 2-Br-(diCYS)HQ caused elevations in blood urea nitrogen (BUN) concentrations and increases in the urinary excretion of glucose, lactate dehydrogenase (LDH), and γ-glutamyl transpeptidase (γ-GT) at a dose of 25 μmol/kg (iv). In contrast, 2-Br-(diNAC)HQ caused significant elevations in BUN at 100 μmol/kg and glucosuria and enzymuria at 50 μmol/kg. 2-Br-3-(CYS)HQ and 2-Br-5&6-(CYS)HQ caused increases in the biochemical indices of nephrotoxicity at doses between 50 and 150 μmol/kg whereas 2-Br-5-(NAC)HQ and 2-Br-6-(NAC)HQ required doses of 150-200 μmol/kg to cause smaller, though significant increases in urinary glucose, γ-GT, and LDH excretion. The histological alterations caused by each thioether were qualitatively similar; only differences in the extent of the renal proximal tubular damage were observed. The initial lesion appears to involve the cells of the medullary ray and the S3M within the outer stripe of the outer medulla. The in vivo nephrotoxicity of 2-Br-(diCYS)HQ, 2-Br-(diNAC)HQ, and the most potent monosubstituted thioethers, 2-Br-5&6-(CYS)HQ and 2-Br-6-(NAC)HQ, was investigated further. Pretreatment of animals with aminooxyacetic acid, an inhibitor of cysteine conjugate β-lyase (β-lyase), had no effect on the toxicity of 2-Br-(diCYS)HQ, partially inhibited the toxicity of 2-Br-5&6-(CYS)HQ, and almost completely protected against the toxicity of both 2-Br-6-(NAC)HQ, and 2-Br-(diNAC)HQ. Thus, the nephrotoxicity of 2-Br-5&6-(CYS)HQ, 2-Br-6-(NAC)HQ, and 2-Br-(diNAC)HQ may be mediated, in part, via their processing by β-lyase. Pretreatment of animals with probenecid, an inhibitor of renal organic anion transport, completely protected against the toxicity of 2-Br-(diNAC)HQ but had no effect on the toxicity of the other thioethers.
AB - The in vivo toxicity of isomeric cystein-S-yl and N-acetylcystein-S-yl conjugates of 2-bromohydroquinone was determined in male Sprague-Dawley rats. 2-Bromo-(dicystein-S-yl)hydroquinone [2-Br-(diCYS)HQ] and 2-bromo-(di-N-acetyl-l-cystein-S-yl)hydroquinone [2-Br-(diNAC)HQ] were considerably more nephrotoxic than their corresponding monosubstituted thioethers and 2-Br-(diCYS)HQ was more nephrotoxic than 2-Br-(diNAC)HQ. 2-Br-(diCYS)HQ caused elevations in blood urea nitrogen (BUN) concentrations and increases in the urinary excretion of glucose, lactate dehydrogenase (LDH), and γ-glutamyl transpeptidase (γ-GT) at a dose of 25 μmol/kg (iv). In contrast, 2-Br-(diNAC)HQ caused significant elevations in BUN at 100 μmol/kg and glucosuria and enzymuria at 50 μmol/kg. 2-Br-3-(CYS)HQ and 2-Br-5&6-(CYS)HQ caused increases in the biochemical indices of nephrotoxicity at doses between 50 and 150 μmol/kg whereas 2-Br-5-(NAC)HQ and 2-Br-6-(NAC)HQ required doses of 150-200 μmol/kg to cause smaller, though significant increases in urinary glucose, γ-GT, and LDH excretion. The histological alterations caused by each thioether were qualitatively similar; only differences in the extent of the renal proximal tubular damage were observed. The initial lesion appears to involve the cells of the medullary ray and the S3M within the outer stripe of the outer medulla. The in vivo nephrotoxicity of 2-Br-(diCYS)HQ, 2-Br-(diNAC)HQ, and the most potent monosubstituted thioethers, 2-Br-5&6-(CYS)HQ and 2-Br-6-(NAC)HQ, was investigated further. Pretreatment of animals with aminooxyacetic acid, an inhibitor of cysteine conjugate β-lyase (β-lyase), had no effect on the toxicity of 2-Br-(diCYS)HQ, partially inhibited the toxicity of 2-Br-5&6-(CYS)HQ, and almost completely protected against the toxicity of both 2-Br-6-(NAC)HQ, and 2-Br-(diNAC)HQ. Thus, the nephrotoxicity of 2-Br-5&6-(CYS)HQ, 2-Br-6-(NAC)HQ, and 2-Br-(diNAC)HQ may be mediated, in part, via their processing by β-lyase. Pretreatment of animals with probenecid, an inhibitor of renal organic anion transport, completely protected against the toxicity of 2-Br-(diNAC)HQ but had no effect on the toxicity of the other thioethers.
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U2 - 10.1016/0041-008X(91)90031-9
DO - 10.1016/0041-008X(91)90031-9
M3 - Article
C2 - 1957313
AN - SCOPUS:0025885446
SN - 0041-008X
VL - 111
SP - 279
EP - 298
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 2
ER -