title: Pulmonary toxicity of 2-methylnaphthalene: lack of a relationship between toxicity, dihydrodiol formation and irreversible binding to cellular macromolecules in DBA/2J mice.
abstract: Intraperitoneal doses of 2-methylnaphthalene (2-MN) have been shown to cause pulmonary toxicity in DBA/2J mice. Pretreatment with the monooxygenase inducers sodium phenobarbital and 3-methylcholanthrene (3-MC) failed to protect the DBA/2J mice from the toxic effect of 2-methylnaphthalene. Pretreatment of DBA/2J mice with the monooxygenase inhibitors, SKF 525-A and piperonyl butoxide also failed to enhance or attentuate the pulmonary lesions. Pulmonary and hepatic microsomes from DBA/2J mice metabolized 2-methylnaphthalene to three dihydrodiols, 2-naphthyl alcohol and other unidentified metabolites. Kidney microsomes produced 2-naphthyl alcohol but no detectable dihydrodiols. In comparison to control animals, hepatic microsomes from animals pretreated with sodium phenobarbital produced more of the least polar dihydrodiol, while amounts of the other two dihydrodiols were unaffected. 3-Methylcholanthrene, piperonyl butoxide and diethylmaleate failed to affect dihydrodiol formation in both pulmonary and hepatic microsomes. After the administration of a lung toxic dose (400 mg/kg, i.p.) of 2-MN, irreversible binding was highest in the liver, followed by the kidney, the lung and lastly skeletal muscle. Of the pretreatments given to the mice, only phenobarbital demonstrated a significant effect, and this elevation was apparent only in the liver. A pulmonary toxic dose of 2-MN (400 mg/kg, i.p.) administered to DBA/2J mice significantly depleted reduced GSH in the liver and lung and to a lesser extent, in the kidney. There appeared no good correlation between the pulmonary toxicity of 2-MN-dihydrodiol and/or alcohol formation or the in vivo irreversible binding to macromolecules. These results are compared with those reported previously in C57BL/6J mice.
mesh_terms: D000818:Animals; D001665:Binding Sites; D004790:Enzyme Induction / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006900:Hydroxylation; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008861:Microsomes / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity*; D010105:Oxygenases / Q000378:metabolism
chemical_list: D046911:Macromolecular Substances; D009281:Naphthalenes; D010105:Oxygenases; D005978:Glutathione; C027384:2-methylnaphthalene