Synthesis and nephrotoxicity of 6-bromo-2,5-dihydroxy-thiophenol.
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.
Monks
T J
TJ
University of Texas System Cancer Center, Smithville.
Highet
R J
RJ
Chu
P S
PS
Lau
S S
SS
D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D006873:Hydroquinones / Q000138:chemical synthesis / Q000378:metabolism* / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011808:Quinone Reductases / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000633:toxicity*
D006873:Hydroquinones; D013438:Sulfhydryl Compounds; C056524:1-thio-6-bromo-2,5-dihydroxybenzene; C056525:1-thio-2,5-dihydroxybenzene; C042377:2-bromohydroquinone; D011808:Quinone Reductases; D005978:Glutathione