METABOLISM OF 2-(GLUTATHIONE-S-YL)HYDROQUINONE AND 2,3,5-(TRIGLUTATHION-S-YL)HYDROQUINONE IN THE IN-SITU PERFUSED RAT-KIDNEY - RELATIONSHIPTO NEPHROTOXICITY

2,3,5-(Triglutathion-S-yl)hydroquinone [2,3,5-(triGSyl)HQ] (20 mu mol/ kg) and 2-(glutathion-S-yl)hydroquinone [2-(GSyl)HQ] (250 mu mol/kg) b oth cause nephrotoxicity when administered to male rats, although the former is considerably more potent than the latter. To address the iss ue 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 mu mol 2,3,5-(triGSyl) HQ into the right renal artery caused a time-dependent elevation in ga mma-glutamyl transpeptidase (gamma-GT) excretion into urine produced b y both the perfused and the contralateral kidneys. At the lower concen tration, gamma-GT excretion was greater from the perfused kidney, wher eas gamma-GT excretion from the per fused and contralateral kidneys wa s the same at the higher concentration. Using HPLC-EC to analyze urine and bile, metabolites of 2,3,5-(triGSyl)HQ (10 mu mol) were observed only within the first 30 min of perfusion. At the lower dose (5 mu mol ) neither parent compound nor metabolites were found in urine or bile. Infusion of 40 mu mol 2-(GSyl)HQ into the right renal artery also cau sed 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 k nown metabolites; 2-(N-acetyl-cystein-S-yl)HQ (9.2 +/- 0.5 mu mol), 2- (cystein-S-ylglycine)HQ (0.8 +/- 0.3 mu mol), and 2-(cystein-S-yl)HQ ( 1.3 +/- 0.3 mu mol). Unchanged 2-(GSyl)HQ was detected in the urine an d bile (0.8 +/- 0.1 mu mol). A greater fraction of the dose (74%) was recovered in urine following infusion of 40 mu mol 2-(GSyl)[C-14]HQ th an of 10 mu mol 2,3,5-(triGSyl)[C-14]HQ (29%). In contrast, a greater fraction of the dose was retained by the kidney following treatment wi th 10 mu mol 2,3,5-(triGSyl)[C-14]HQ than following treatment with 40 mu mol 2-(GSyl)[C-14]HQ (36 and 11%, respectively). This result sugges ts that metabolites derived from 2,3,5-(triGSyl)[C-14]HQ are more reac tive than those derived from 2(GSyl)[C-14]HQ, which is consistent with the finding that 2,3,5-(tricystein-S-yl)hydro quinone exhibits a lowe r oxidation potential than 2-(cystein-S-yl)hydroquinone. Differences i n the reactivity of the metabolites derived from 2,3,5-(triGSyl)[C-14] HQ and 2-(GSyl)[C-14]HQ probably account for the more potent nephrotox icity of 2,3,5-(triGSyl)HQ. (C) 1994 Academic Press, Inc.