Carcinogenicity of a nephrotoxic metabolite of the "nongenotoxic" carcinogen hydroquinone

Hydroquinone (HQ) is a potential human carcinogen to which many people are exposed. HQ generally tests negative in standard mutagenicity assays, makin g it a "nongenotoxic" carcinogen whose 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 carcinogen in the kidn ey, 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) t umor suppressor gene, which makes them highly susceptible to the developmen t of renal tumors. As early as 3 months after the initiation of treatment ( 2.5 mu mol/kg, ip), TGHQ-treated rats developed numerous toxic tubular dysp lasias of a form rarely present in vehicle-treated rats. These preneoplasti c lesions are believed to represent early transformation within tubules und ergoing regeneration after injury by TGHQ, and adenomas subsequently arose within these lesions. After treatment for 10 months (2.5 mu mol/kg for 4 mo nths followed by 3.5 mu mol/kg for 6 months), there were 6-, 7-, and 10-fol d more basophilic dysplasias, adenomas, and renal cell carcinomas, respecti vely, in TGHQ-treated animals than in controls. Most of these lesions were in the region of TGHQ-induced acute renal injury, the outer stripe of the o uter medulla. Loss of heterozygosity (LOH) at the Tsc-2 locus was demonstra ted in both the toxic tubular dysplasias and tumors from rats treated with TGHQ for 10 months, consistent with TGHQ-induced loss of tumor suppressor f unction of the Tsc-2 gene. Thus, although HQ is generally considered a nong enotoxic carcinogen, our data suggest that HQ nephrocarcinogenesis is proba bly mediated by the formation of the quantitatively minor yet potent nephro toxic metabolite TGHQ, which induces sustained regenerative hyperplasia, lo ss of tumor suppressor gene function, and the subsequent formation of renal adenomas and carcinomas. In addition, our data demonstrate that assumption s regarding mechanisms of action of nongenotoxic carcinogens should be cons idered carefully in the absence of data on the profiles of metabolites gene rated by these compounds in specific target organs for tumor induction.