Jpn. J. Pharmacol. 86 (3), 302-309 (2001)

Mechanism of 7,12-Dimethylbenz[a]anthracene-Induced Immunotoxicity: Role of Metabolic Activation at the Target Organ

Masaaki Miyata1,*, Masayuki Furukawa1,#, Koichi Takahashi1, Frank J. Gonzalez2 and Yasushi Yamazoe1

1Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
2Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA

*Corresponding author. FAX: +81-22-217-6826, E-mail:
#Present address: Otsuka Pharmaceutical Co., Ltd., Kawauchi-cho, Tokushima 771-0192, Japan

Abstract: The polycyclic aromatic hydrocarbon, 7,12-dimethylbenz[a]anthracene (DMBA), is an immunosuppressor as well as a potent organ-specific carcinogen. To understand the organ-specific mechanism of DMBA-induced lymphoid toxicity, aryl hydrocarbon-nonresponsive mice and microsomal epoxide hydrolase (mEH)-null mice were analyzed. DMBA caused a dose-dependent decrease in spleen weights, but not the thymus weights in aryl hydrocarbon-nonresponsive mice. On the other hand, both spleen and thymus weights were decreased to less than a half in wild-type mice exposed to 30 mg/kg of DMBA. In contrast, no decrease was detected in spleen weights of mEH-null mice exposed to up to 100 mg/kg of DMBA, while thymus weights were markedly lower. Responses to the B-cell mitogen lipopolysaccharide and to T-cell mitogen phytohemagglutinin were nearly completely abolished in splenocytes isolated from wild-type mice treated with 100 mg/kg of DMBA. These responses were decreased, but maintained in splenocytes isolated from mEH-null mice treated with DMBA. Two DMBA metabolites dependent on mEH including DMBA-3,4-diol were detected in an HPLC chromatogram of spleen microsomes isolated from wild-type mice, but not those from mEH-null mice. These results suggest the involvement of mEH in splenic activation of DMBA for immunotoxicity and the difference for the DMBA-induced lymphoid toxicity between spleen and thymus.

Keywords: 7,12-Dimethylbenz[a]anthracene, Immunotoxicity, Microsomal epoxide hydrolase, Spleen, Null-mouse
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