The mercapturic acid biotransformation pathway of hexachlorohenzene is notinvolved in the induction of splenomegaly, or skin and lung lesions in theBrown Norway rat

Involvement of the mercapturic acid pathway in the induction of splenomegal y and skin and lung pathology by hexachlorobenzene (HCB) in the rat was inv estigated by seeking to determine whether pentachloronitrobenzene (PCNB) ha s the same inflammatory effects as HCB, since both compounds are directly c onjugated to glutathione, and further processed into the same mercapturic a cid metabolites which are excreted via the urine. Female Brown Norway (BN/ SsNO1aHsd) rats at 3 to 4 weeks of age were orally exposed to diets with or without supplementation with 450 mg HCB or equimolar (467 mg) or higher (9 34 mg) amounts of PCNB per kilogram of diet over 4 weeks. Gross skin lesion development and body weight gains were assessed during exposure and spleen and liver weights as well as histopathologic changes in skin and lung were assessed after exposure. After 3 weeks of exposure, urinary metabolites of the mercapturic acid and oxidative biotransformation pathways were identif ied using high-performance liquid chromatography (HPLC) and liquid chromato graphy-mass spectrometry (LC-MS). Oral exposure of the rats to 450 mg/kg HC B resulted in an increase in relative spleen and liver weights as well as i n the development of skin and lung pathology in the absence of overall live r toxicity. Equimolar or higher concentrations of PCNB caused none of these effects. Urinary levels of the mercapturic acid N-acetyl-S-(pentachlorophe nyl)-cysteine (PCP-NAC), were comparable in HCB- and PCNB-treated rats. Lev els of closely related methylsulfide derivatives of PCP-NAC, also generated via the same mercapturic acid pathway, appeared to be significantly higher in PCNB- than in HCB-treated rats, whereas the reverse was true for the ur inary levels of the oxidative metabolite pentachlorophenol (PCP). Thus, res ults indicate that metabolites of the mercapturic acid pathway are not invo lved in the induction of splenomegaly and skin and lung pathology caused by HCB exposure in BN rats and that the main urinary metabolite of HCB in the se BN rats is PCP. Since PCP itself, as well as other cytochrome P450-deriv ed metabolites from HCB, are not likely to be involved in the induction of splenomegaly and skin and lung pathology, it is suggested that either the p arent compound HCB or as-yet-unidentified non-P450-generated metabolites ar e involved in these inflammatory effects of HCB.