Differences in the localization and extent of the renal proximal tubular necrosis caused by mercapturic acid and glutathione conjugates of 1,4-naphthoquinone and menadione.
We have previously demonstrated that administration of various benzoquinol-glutathione (GSH) conjugates to rats causes renal proximal tubular necrosis and the initial lesion appears to lie within that portion of the S3 segment within the outer stripe of the outer medulla (OSOM). The toxicity may be a consequence of oxidation of the quinol conjugate to the quinone followed by covalent binding to tissue macromolecules. We have therefore synthesized the GSH and N-acetylcysteine conjugates of 2-methyl-1,4-naphthoquinone (menadione) and 1,4-naphthoquinone. The resulting conjugates have certain similarities to the benzoquinol-GSH conjugates, but the main difference is that reaction with the thiol yields a conjugate which remains in the quinone form. 2-Methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone caused a dose-dependent (50-200 mumol/kg) necrosis of the proximal tubular epithelium. The lesion involved the terminal portion of the S2 segment and the S3 segment within the medullary ray. At the lower doses, that portion of the S3 segment in the outer stripe of the outer medulla displayed no evidence of necrosis. In contrast, 2-methyl-3-(glutathion-S-yl)-1,4-naphthoquinone (200 mumol/kg) caused no apparent histological alterations to the kidney. 2-(Glutathion-S-yl)-1,4-naphthoquinone and 2,3-(diglutathion-S-yl)-1,4-naphthoquinone (200 mumol/kg) were relatively weak proximal tubular toxicants and the lesion involved the S3 segment at the junction of the medullary ray and the OSOM. A possible reason(s) for the striking difference in the toxicity of the N-acetylcysteine conjugate of menadione, as opposed to the lack of toxicity of the GSH conjugate of menadione, is discussed. The basis for the localization of the lesion caused by 2-methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone requires further study.
Lau
S S
SS
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas, Austin.
Jones
T W
TW
Highet
R J
RJ
Hill
B A
BA
Monks
T J
TJ
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D001806:Blood Urea Nitrogen; D005978:Glutathione / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000633:toxicity; D007672:Kidney Cortex / Q000187:drug effects / Q000473:pathology; D007679:Kidney Medulla / Q000187:drug effects / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D014812:Vitamin K / Q000633:toxicity*
D009285:Naphthoquinones; C064787:2,3-(di-glutathion-S-yl)-1,4-naphthoquinone; C064785:3-(glutathion-S-yl)-1,4-naphthoquinone; D014812:Vitamin K; C064788:2-methyl-3-(N-acetylcystein-S-yl)-1,4-naphthoquinone; C040137:2-methyl-3-glutathionyl-1,4-naphthoquinone; D005978:Glutathione; D000111:Acetylcysteine