Metabolism of 2-(Glutathione-S-yl)Hydroquinone and 2,3,5-(Triglutathion-S-yl)Hydroquinone in the in Situ Perfused Rat Kidney

Relationship to Nephrotoxicity

B. A. Hill, K. L. Davison, D. M. Dulik, Terrence Monks, Serrine Lau

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] (20 μmol/kg) and 2-(glutathion-S-yl)hydroquinone [2-(GSyl)HQ] (250 μmol/kg) both cause nephrotoxicity when administered to male rats, although the former is considerably more potent than the latter. To address the issue of the differential potency of these conjugates we investigated the metabolism and toxicity of 2,3,5-(triGSyl)HQ and 2-(GSyl)HQ in the in situ perfused rat kidney. Infusion of 5 and 10 μmol 2,3,5-(triGSyl)HQ into the right renal artery caused a time-dependent elevation in γ-glutamyl transpeptidase (γ-GT) excretion into urine produced by both the perfused and the contralateral kidneys. At the lower concentration, γ-GT excretion was greater from the perfused kidney, whereas γ-GT excretion from the perfused and contralateral kidneys was the same at the higher concentration. Using HPLC-EC to analyze urine and bile, metabolites of 2,3,5-(triGSyl)HQ (10 μmol) were observed only within the first 30 min of perfusion. At the lower dose (5 μmol) neither parent compound nor metabolites were found in urine or bile. Infusion of 40 μmol 2-(GSyl)HQ into the right renal artery also caused a time-dependent excretion of γ-GT into urine: excretion being greater from the perfused kidney. HPLC-EC analysis of urine and bile from 2-(GSyl)HQ perfused kidneys demonstrated the formation of three known metabolites; 2-(N-acetyl-cystein-S-yl)HQ (9.2 ± 0.5 μmol), 2-(cystein-S-ylglycine)HQ (0.8 ± 0.3 μmol), and 2-(cystein-S-yl)HQ (1.3 ± 0.3 μmol). Unchanged 2-(GSyl)HQ was detected in the urine and bile (0.8 ± 0.1 μmol). A greater fraction of the dose (74%) was recovered in urine following infusion of 40 μmol 2-(GSyl)[14C]HQ than of 10 μmol 2,3,5-(triGSyl)[14C]HQ (29%). In contrast, a greater fraction of the dose was retained by the kidney following treatment with 10 μmol 2,3,5-(triGSyl)[14C]HQ than following treatment with 40 μmol 2-(GSyl)[14C]HQ (36 and 11%, respectively). This result suggests that metabolites derived from 2,3,5-(triGSyl)[14C]HQ are more reactive than those derived from 2(GSyl)[14C]HQ, which is consistent with the finding that 2,3,5-(tricystein-S-yl)hydro quinone exhibits a lower oxidation potential than 2-(cystein-S-yl)hydroquinone. Differences in the reactivity of the metabolites derived from 2,3,5-(triGSyl)[14C]HQ and 2-(GSyl)[14C]HQ probably account for the more potent nephrotoxicity of 2,3,5-(triGSyl)HQ.

Original languageEnglish (US)
Pages (from-to)121-132
Number of pages12
JournalToxicology and Applied Pharmacology
Volume129
Issue number1
DOIs
StatePublished - Nov 1994
Externally publishedYes

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Metabolism
Glutathione
Rats
Metabolites
Kidney
Urine
Bile
Renal Artery
gamma-Glutamyltransferase
High Pressure Liquid Chromatography
Toxicity
2,3,5-(triglutathion-S-yl)hydroquinone
hydroquinone
Oxidation
Perfusion

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

@article{9ab5f0baf81a49a9a4de0c99cf9de7c3,
title = "Metabolism of 2-(Glutathione-S-yl)Hydroquinone and 2,3,5-(Triglutathion-S-yl)Hydroquinone in the in Situ Perfused Rat Kidney: Relationship to Nephrotoxicity",
abstract = "2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] (20 μmol/kg) and 2-(glutathion-S-yl)hydroquinone [2-(GSyl)HQ] (250 μmol/kg) both cause nephrotoxicity when administered to male rats, although the former is considerably more potent than the latter. To address the issue of the differential potency of these conjugates we investigated the metabolism and toxicity of 2,3,5-(triGSyl)HQ and 2-(GSyl)HQ in the in situ perfused rat kidney. Infusion of 5 and 10 μmol 2,3,5-(triGSyl)HQ into the right renal artery caused a time-dependent elevation in γ-glutamyl transpeptidase (γ-GT) excretion into urine produced by both the perfused and the contralateral kidneys. At the lower concentration, γ-GT excretion was greater from the perfused kidney, whereas γ-GT excretion from the perfused and contralateral kidneys was the same at the higher concentration. Using HPLC-EC to analyze urine and bile, metabolites of 2,3,5-(triGSyl)HQ (10 μmol) were observed only within the first 30 min of perfusion. At the lower dose (5 μmol) neither parent compound nor metabolites were found in urine or bile. Infusion of 40 μmol 2-(GSyl)HQ into the right renal artery also caused a time-dependent excretion of γ-GT into urine: excretion being greater from the perfused kidney. HPLC-EC analysis of urine and bile from 2-(GSyl)HQ perfused kidneys demonstrated the formation of three known metabolites; 2-(N-acetyl-cystein-S-yl)HQ (9.2 ± 0.5 μmol), 2-(cystein-S-ylglycine)HQ (0.8 ± 0.3 μmol), and 2-(cystein-S-yl)HQ (1.3 ± 0.3 μmol). Unchanged 2-(GSyl)HQ was detected in the urine and bile (0.8 ± 0.1 μmol). A greater fraction of the dose (74{\%}) was recovered in urine following infusion of 40 μmol 2-(GSyl)[14C]HQ than of 10 μmol 2,3,5-(triGSyl)[14C]HQ (29{\%}). In contrast, a greater fraction of the dose was retained by the kidney following treatment with 10 μmol 2,3,5-(triGSyl)[14C]HQ than following treatment with 40 μmol 2-(GSyl)[14C]HQ (36 and 11{\%}, respectively). This result suggests that metabolites derived from 2,3,5-(triGSyl)[14C]HQ are more reactive than those derived from 2(GSyl)[14C]HQ, which is consistent with the finding that 2,3,5-(tricystein-S-yl)hydro quinone exhibits a lower oxidation potential than 2-(cystein-S-yl)hydroquinone. Differences in the reactivity of the metabolites derived from 2,3,5-(triGSyl)[14C]HQ and 2-(GSyl)[14C]HQ probably account for the more potent nephrotoxicity of 2,3,5-(triGSyl)HQ.",
author = "Hill, {B. A.} and Davison, {K. L.} and Dulik, {D. M.} and Terrence Monks and Serrine Lau",
year = "1994",
month = "11",
doi = "10.1006/taap.1994.1235",
language = "English (US)",
volume = "129",
pages = "121--132",
journal = "Toxicology and Applied Pharmacology",
issn = "0041-008X",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Metabolism of 2-(Glutathione-S-yl)Hydroquinone and 2,3,5-(Triglutathion-S-yl)Hydroquinone in the in Situ Perfused Rat Kidney

T2 - Relationship to Nephrotoxicity

AU - Hill, B. A.

AU - Davison, K. L.

AU - Dulik, D. M.

AU - Monks, Terrence

AU - Lau, Serrine

PY - 1994/11

Y1 - 1994/11

N2 - 2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] (20 μmol/kg) and 2-(glutathion-S-yl)hydroquinone [2-(GSyl)HQ] (250 μmol/kg) both cause nephrotoxicity when administered to male rats, although the former is considerably more potent than the latter. To address the issue of the differential potency of these conjugates we investigated the metabolism and toxicity of 2,3,5-(triGSyl)HQ and 2-(GSyl)HQ in the in situ perfused rat kidney. Infusion of 5 and 10 μmol 2,3,5-(triGSyl)HQ into the right renal artery caused a time-dependent elevation in γ-glutamyl transpeptidase (γ-GT) excretion into urine produced by both the perfused and the contralateral kidneys. At the lower concentration, γ-GT excretion was greater from the perfused kidney, whereas γ-GT excretion from the perfused and contralateral kidneys was the same at the higher concentration. Using HPLC-EC to analyze urine and bile, metabolites of 2,3,5-(triGSyl)HQ (10 μmol) were observed only within the first 30 min of perfusion. At the lower dose (5 μmol) neither parent compound nor metabolites were found in urine or bile. Infusion of 40 μmol 2-(GSyl)HQ into the right renal artery also caused a time-dependent excretion of γ-GT into urine: excretion being greater from the perfused kidney. HPLC-EC analysis of urine and bile from 2-(GSyl)HQ perfused kidneys demonstrated the formation of three known metabolites; 2-(N-acetyl-cystein-S-yl)HQ (9.2 ± 0.5 μmol), 2-(cystein-S-ylglycine)HQ (0.8 ± 0.3 μmol), and 2-(cystein-S-yl)HQ (1.3 ± 0.3 μmol). Unchanged 2-(GSyl)HQ was detected in the urine and bile (0.8 ± 0.1 μmol). A greater fraction of the dose (74%) was recovered in urine following infusion of 40 μmol 2-(GSyl)[14C]HQ than of 10 μmol 2,3,5-(triGSyl)[14C]HQ (29%). In contrast, a greater fraction of the dose was retained by the kidney following treatment with 10 μmol 2,3,5-(triGSyl)[14C]HQ than following treatment with 40 μmol 2-(GSyl)[14C]HQ (36 and 11%, respectively). This result suggests that metabolites derived from 2,3,5-(triGSyl)[14C]HQ are more reactive than those derived from 2(GSyl)[14C]HQ, which is consistent with the finding that 2,3,5-(tricystein-S-yl)hydro quinone exhibits a lower oxidation potential than 2-(cystein-S-yl)hydroquinone. Differences in the reactivity of the metabolites derived from 2,3,5-(triGSyl)[14C]HQ and 2-(GSyl)[14C]HQ probably account for the more potent nephrotoxicity of 2,3,5-(triGSyl)HQ.

AB - 2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] (20 μmol/kg) and 2-(glutathion-S-yl)hydroquinone [2-(GSyl)HQ] (250 μmol/kg) both cause nephrotoxicity when administered to male rats, although the former is considerably more potent than the latter. To address the issue of the differential potency of these conjugates we investigated the metabolism and toxicity of 2,3,5-(triGSyl)HQ and 2-(GSyl)HQ in the in situ perfused rat kidney. Infusion of 5 and 10 μmol 2,3,5-(triGSyl)HQ into the right renal artery caused a time-dependent elevation in γ-glutamyl transpeptidase (γ-GT) excretion into urine produced by both the perfused and the contralateral kidneys. At the lower concentration, γ-GT excretion was greater from the perfused kidney, whereas γ-GT excretion from the perfused and contralateral kidneys was the same at the higher concentration. Using HPLC-EC to analyze urine and bile, metabolites of 2,3,5-(triGSyl)HQ (10 μmol) were observed only within the first 30 min of perfusion. At the lower dose (5 μmol) neither parent compound nor metabolites were found in urine or bile. Infusion of 40 μmol 2-(GSyl)HQ into the right renal artery also caused a time-dependent excretion of γ-GT into urine: excretion being greater from the perfused kidney. HPLC-EC analysis of urine and bile from 2-(GSyl)HQ perfused kidneys demonstrated the formation of three known metabolites; 2-(N-acetyl-cystein-S-yl)HQ (9.2 ± 0.5 μmol), 2-(cystein-S-ylglycine)HQ (0.8 ± 0.3 μmol), and 2-(cystein-S-yl)HQ (1.3 ± 0.3 μmol). Unchanged 2-(GSyl)HQ was detected in the urine and bile (0.8 ± 0.1 μmol). A greater fraction of the dose (74%) was recovered in urine following infusion of 40 μmol 2-(GSyl)[14C]HQ than of 10 μmol 2,3,5-(triGSyl)[14C]HQ (29%). In contrast, a greater fraction of the dose was retained by the kidney following treatment with 10 μmol 2,3,5-(triGSyl)[14C]HQ than following treatment with 40 μmol 2-(GSyl)[14C]HQ (36 and 11%, respectively). This result suggests that metabolites derived from 2,3,5-(triGSyl)[14C]HQ are more reactive than those derived from 2(GSyl)[14C]HQ, which is consistent with the finding that 2,3,5-(tricystein-S-yl)hydro quinone exhibits a lower oxidation potential than 2-(cystein-S-yl)hydroquinone. Differences in the reactivity of the metabolites derived from 2,3,5-(triGSyl)[14C]HQ and 2-(GSyl)[14C]HQ probably account for the more potent nephrotoxicity of 2,3,5-(triGSyl)HQ.

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