Hydroquinone (HQ) is a potential human carcinogen to which many people are exposed. HQgenerally tests negative in standard mutagenicity assays, making it a "nongenotoxic" carcinogenwhose mechanism of action remains unknown. HQ is metabolized to 2,3,5-tris(glutathion-
S-yl)HQ (TGHQ), a potent toxic and redox active compound. To determine if TGHQ is a carcinogenin the kidney, TGHQ was administered to Eker rats (2 months of age) for 4 or 10 months.Eker rats carry a germline mutation in the tuberous sclerosis 2 (
Tsc-2) tumor suppressor gene,which makes them highly susceptible to the development of renal tumors. As early as 4 monthsafter the initiation of treatment (2.5
mol/kg, ip), TGHQ-treated rats developed numerous toxictubular dysplasias of a form rarely present in vehicle-treated rats. These preneoplastic lesionsare believed to represent early transformation within tubules undergoing regeneration afterinjury by TGHQ, and adenomas subsequently arose within these lesions. After treatment for10 months (2.5
mol/kg for 4 months followed by 3.5
mol/kg for 6 months), there were 6-, 7-,and 10-fold more basophilic dysplasias, adenomas, and renal cell carcinomas, respectively, inTGHQ-treated animals than in
controls. Most of these lesions were in the
region of TGHQ-induced acute renal injury, the outer stripe of the outer medulla. Loss of heterozygosity (LOH)at the
Tsc-2 locus was demonstrated in both the toxic tubular dysplasias and tumors fromrats treated with TGHQ for 10 months, consistent with TGHQ-induced loss of tumor suppressorfunction of the
Tsc-2 gene. Thus, although HQ is generally considered a nongenotoxiccarcinogen, our data suggest that HQ nephrocarcinogenesis is probably mediated by theformation of the quantitatively minor yet potent nephrotoxic metabolite TGHQ, which inducessustained regenerative hyperplasia, loss of tumor suppressor gene function, and the subsequentformation of renal adenomas and carcinomas. In addition, our data demonstrate thatassumptions regarding mechanisms of action of nongenotoxic carcinogens should be consideredcarefully in the absence of data on the profiles of metabolites generated by these compoundsin specific target organs for tumor induction.