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  • Title: Metabolism of 2-(glutathion-S-yl)hydroquinone and 2,3,5- (triglutathion-S-yl)hydroquinone in the in situ perfused rat kidney: relationship to nephrotoxicity.
    Author: Hill BA, Davison KL, Dulik DM, Monks TJ, Lau SS.
    Journal: Toxicol Appl Pharmacol; 1994 Nov; 129(1):121-32. PubMed ID: 7974485.
    Abstract:
    2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] (20 mumol/kg) and 2-(glutathion-S-yl)hydroquinone [2-(GSyl)-HQ] (250 mumol/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 mumol 2,3,5-(triGSyl)HQ into the right renal artery caused a time-dependent elevation in gamma-glutamyl transpeptidase (gamma-GT) excretion into urine produced by both the perfused and the contralateral kidneys. At the lower concentration, gamma-GT excretion was greater from the perfused kidney, whereas gamma-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 mumol) were observed only within the first 30 min of perfusion. At the lower dose (5 mumol) neither parent compound nor metabolites were found in urine or bile. Infusion of 40 mumol 2-(GSyl)HQ into the right renal artery also caused a time-dependent excretion of gamma-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 mumol). 2-(cystein-S-ylglycine)HQ (0.8 +/- 0.3 mumol), and 2-(cystein-S-yl)HQ (1.3 +/- 0.3 mumol). Unchanged 2-(GSyl)HQ was detected in the urine and bile (0.8 +/- 0.1 mumol). A greater fraction of the dose (74%) was recovered in urine following infusion of 40 mumol 2-(GSyl)[14C]HQ than of 10 mumol 2,3,5-(triGSyl)[14C]HQ (29%). In contrast, a greater fraction of the dose was retained by the kidney following treatment with 10 mumol 2,3,5-(triGSyl)[14C]HQ than following treatment with 40 mumol 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)hydroquinone 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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