Synthesis and nephrotoxicity of 6-bromo-2,5-dihydroxythiophenol

Terrence Monks, R. J. Highet, P. S. Chu, Serrine Lau

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)15-22
Number of pages8
JournalMolecular Pharmacology
Volume34
Issue number1
StatePublished - 1988
Externally publishedYes

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Blood Urea Nitrogen
Glutathione
Kidney
1-thio-6-bromo-2,5-dihydroxybenzene
thiophenol
Transaminases
Pyruvic Acid
Sulfhydryl Compounds
NAD
Toxicology
Cysteine
Glutamic Acid
Mass Spectrometry
Oxidoreductases
Magnetic Resonance Spectroscopy
Pathology
Liver
Serum
benzoquinone
2-bromohydroquinone

ASJC Scopus subject areas

  • Pharmacology

Cite this

Synthesis and nephrotoxicity of 6-bromo-2,5-dihydroxythiophenol. / Monks, Terrence; Highet, R. J.; Chu, P. S.; Lau, Serrine.

In: Molecular Pharmacology, Vol. 34, No. 1, 1988, p. 15-22.

Research output: Contribution to journalArticle

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