Synthesis and nephrotoxicity of 6-bromo-2,5-dihydroxy-thiophenol

• Published in: Molecular pharmacology Vol. 34; no. 1; p. 15
• Main Authors: Monks, T J, Highet, R J, Chu, P S, Lau, S S
• Format: Journal Article
• Language: English
• Published: United States 01-07-1988
• Subjects: Animals; Glutathione - metabolism; Hydroquinones - chemical synthesis; Hydroquinones - metabolism; Hydroquinones - toxicity; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Magnetic Resonance Spectroscopy; Male; Quinone Reductases - analysis; Rats; Rats, Inbred Strains; Structure-Activity Relationship; Sulfhydryl Compounds - chemical synthesis; Sulfhydryl Compounds - toxicity
• ISSN: 0026-895X

The formation of potentially reactive thiols has been postulated to play a role in the nephrotoxicity caused by a number of glutathione and/or cysteine conjugates. However, the inherent reactivity of such compounds has precluded both their identification in biological systems and a determination of their actual toxicity. To this end we have synthesized 6-bromo-2,5-dihydroxy-thiophenol as a putative metabolite of nephrotoxic 2-bromohydroquinone-glutathione conjugates. The compound was prepared by the addition of sodium thiosulfate to 2-bromo-1,4-benzoquinone followed by reduction of the S-arylthiosulfate to the thiophenol. 2,5-Dihydroxy-thiophenol was similarly prepared. Structural identification was confirmed by mass spectroscopy and nuclear magnetic resonance spectroscopy. Administration of 6-bromo-2,5-dihydroxy-thiophenol to rats (0.35 mmol/kg; intraperitoneally) caused an increase in blood urea nitrogen and histological alterations similar to those observed after 2-bromo-(diglutathion-S-yl)hydroquinone administration. 2,5-Dihydroxy-thiophenol was also nephrotoxic but at a dose of 0.6 mmol/kg. In contrast, no effects on liver pathology were observed after administration of either 6-bromo-2,5-dihydroxy-thiophenol or 2,5-dihydroxy-thiophenol and serum glutamate pyruvate transaminase levels were normal. Neither 2-, 3-, nor 4-bromothiophenol had any effect on blood urea nitrogen at doses between 0.2 and 0.8 mmol/kg (intraperitoneally) and no apparent alterations were seen in kidney slices prepared from bromothiophenol-treated rats. These findings suggest that the quinone function of 6-bromo-2,5-dihydroxy-thiophenol is necessary for the expression of toxicity. In this respect, the lower activity of NAD(P)H quinone oxidoreductase (EC 1.6.99.2) in renal cortex may be of toxicological significance.