The human use of quinones dates to antiquity when crude plant preparations containing a variety of anthraquinones as the active constituents were used as purgatives and emetics. Pigments prepared from henna and madder were used as cosmetics and dyes and contained derivatives of 1,4-naphthoquinone (NQ) and anthraquinone respectively. The active ingredient of henna, lawsone (2-hydroxy-1,4-NQ), is still widely available in U.S. supermarkets as a """"""""natural"""""""" hair dye. The isomeric juglone (5-hydroxy-1,4-NQ) which is found in walnut hulls and leaves is highly toxic and behaves as a tumor promoter in mouse skin. The quinones of polycyclic hydrocarbons are prevalent as environ-mental contaminants and provide an additional current source of human exposure to quinones. In 1984, annual U.S. production of hydroquinone (HQ) was estimated to be 34 million pounds. HQ has several applications including its use as a developer in photography, as an antioxidant in the rubber industry, and as an intermediate in the manufacture of other antioxidants. HQ, and products containing HQ, are used as depigmenting agents for the treatment of a variety of skin disorders. HQ has also been identified and quantified in the smoke of nonfiltered cigarettes (88-155 mg/cig.). During prior grant years we have shown that oxidation of HQ to 1,4-benzoquinone and reaction with glutathione (GSH) gives rise to a mixture of multi-GSH substituted HQ conjugates, which are potent renal proximal tubule toxicants when administered to rats. In particular, 2,3,5-(triGSyl)HQ (10-20 mumol/kg) is a potent nephrotoxicant. Concomitant with our findings, the National Toxicology Program reported that HQ was both acutely nephrotoxic in male and female rats exhibited evidence of nephrocarcinogenic activity in male F344/N rats, but not in female rats nor male and female B6C3F1 mice. Whether HQ-GSH conjugates play a role in both the acute and chronic renal effects of HQ is not known. However, 2-(GSyl)HQ, 2,3-(diGSyl)HQ, 2,5-(diGSyl)HQ, 2,6-(diGSyl)HQ and 2,3,5-(triGSyl)HQ have all been identified as in vivo and in vitro metabolites of HQ in amounts sufficient to contribute to the acute and chronic effects of HQ on the kidney. Neither the mechanism of HQ-mediated nephrotoxicity in F344/N rats, nor the basis for the species differences in the nephrocarcinogenic response are known. Species differences also exist in the susceptibility to 2,3,5-(triGSyl)HQ mediated nephrotoxicity, the biochemical and physiological basis for which remains obscure. We therefore propose to (i) investigate HQ oxidation and HQ-thioether formation and disposition in various species, (ii) determine the basis for the species differences in HQ-mediated nephrotoxicity and (iii) delineate the role of HQ-GSH conjugates and nephrotoxicity in HQ-mediated nephrocarcinogenesis. These questions have important relevance to human health since familial predisposition to renal cancer exists in humans but few animal models to study this exist. A considerable body of literature now indicates that a variety of quinone-thioethers possess biological and toxicological activity. The ubiquitous nature of quinones and the high concentrations of GSH within cells virtually guarantees that humans will be exposed to the resulting quinone thioethers. Studies on factors regulating species susceptibility to these compounds will therefore be of toxicological significance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Toxicology Subcommittee 2 (TOX)
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University of Texas Austin
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Cohen, Jennifer D; Labenski, Matthew; Mastrandrea, Nicholas J et al. (2016) Transcriptional and post-translational modifications of B-Raf in quinol-thioether induced tuberous sclerosis renal cell carcinoma. Mol Carcinog 55:1243-50
Cohen, Jennifer D; Tham, Kimberly Y; Mastrandrea, Nicholas J et al. (2011) cAMP-dependent cytosolic mislocalization of p27(kip)-cyclin D1 during quinol-thioether-induced tuberous sclerosis renal cell carcinoma. Toxicol Sci 122:361-71
Cohen, Jennifer D; Gard, Jaime M C; Nagle, Raymond B et al. (2011) ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether-induced tuberous sclerosis renal cell carcinoma. Toxicol Sci 124:75-87