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Tissue-Specific Metabolism of Benzene in Zymbal Gland and Other Solid Tumor Target Tissues in Rats

Stonybrook Laboratories Inc., Princeton, New Jersey, U.S.A.

Charles E. Lambert

Stonybrook Laboratories Inc., Princeton, New Jersey, U.S.A.

J. Ralph Meeks

Environmental Health and Safety Department, Mobil Oil Corporation, Princeton, New Jersey, U.S.A.

Paul A. Naro

Stonybrook Laboratories Inc., Princeton, New Jersey, U.S.A.

Carl R. Mackerer

Stonybrook Laboratories Inc., Princeton, New Jersey, U.S.A.

In vitro studies were carried out to investigate whether target organ susceptibility to benzene-induced solid tumor formation is governed by tissue-specific differences in metabolism. The ability of several target and nontarget tissues to deconjugate and conjugate polar metabolites, to metabolize benzene to phenolic metabolites, to carry out peroxidative biotransformations, and to trap tissue glutathione was evaluated. The Zymbal gland, the organ most sensitive to benzene-induced tumorigenicity, showed extensive phenyl- and aryl-sulfatase activity but no phenol sulfoconjugating activity. Similarly, oral cavity tissue, mammary gland, and bone marrow showed sulfatase activity but lacked sulfotransferase activity. Sulfatase-mediated hydrolysis such as that observed in the Zymbal gland may represent an important pathway by which polar metabolites are shunted from urinary or biliary excretion as their sulfates to delivery to target tissues as phenolic or potentially reactive metabolite(s). Zymbal gland, nasal and oral cavity, and mammary gland tissue homogenates (10,000 g supernatant) all possess oxidative capability to metabolize benzene to phenol, hydroquinone, and catechol. Nasal cavity homogenates produced two-to eightfold higher levels of phenol, hydroquinone, and catechol from benzene than did liver homogenates. Zymbal gland, bone marrow, and oral cavity homogenates, when incubated with hydroquinone and glutathione, produced high levels of 2-(S-glutathionyl)hydroquinone, indirectly indicating the production of 1,4-benzoquinone, a reactive intermediate implicated in benzene toxicity. Peroxidases have been proposed to mediate the oxidation of p-hydroquinone to 1,4-benzoquinone. The Zymbal gland, nasal and oral cavities, mammary gland, and bone marrow all were found to possess greater peroxidase activity than contrasting nontarget tissues did. The metabolic capabilities of target tissues, including the ability to hydrolyze sulfate conjugates to free phenolic compounds, to oxidize benzene to phenolic metabolites, to bioactivate hydroquinone to a reactive intermediate, and to carry out peroxidative reactions may offer possible explanations for the greater susceptibility of these sites to benzene-induced tumorigenicity. Transport of sulfate conjugates and their release via hydrolysis (e.g., through sulfatase action) ("sulfate shunting") and subsequent oxidation (e.g., through peroxidase action) may represent a novel mechanistic pathway by which potentially reactive benzene metabolites can gain access to target sites and initiate critical genotoxic events.

Key Words: Benzene • Metabolites • Tissue • specific metabolism • Zymbal gland-Phenylsul • fate • Sulfatase • Sulfate shunt • Peroxidase • Mechanism of toxicity

International Journal of Toxicology, Vol. 14, No. 1, 40-60 (1995)
DOI: 10.3109/10915819509008680


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