Inhibition of Rat Respiratory-Tract Cytochrome P-450 Activity After Acute Low-Level m-Xylene Inhalation: Role in 1-Nitronaphthalene Toxicity

Abstract

The xylenes are commonly used industrial solvents that have been shown to inhibit cytochromeP-450 (CYP450) activities in an organ- and isozyme-specific pattern. This study examinedthe dose-response and durational effects of m-xylene inhalation on cytochrome P-450 activitiesin the respiratory tract and liver as well as the effects of these CYP450 alterations on1-nitronaphthalene (1-NN)-induced respiratory or hepatic toxicity. After m-xylene inhalationexposure there was a dose-related inhibition of all nasal mucosa CYPs examined. At 300 ppm,inhibition was sustained up to 2 days after exposure, but on day 5 all CYP activities were increased.There was also dose-related inhibition of lung CYPs 2B1, 2E1, and 4B1. The activitiesof these CYPs returned to those of control by day 2 but lung CYP 2B1 was increased 5 daysfollowing m-xylene exposure. Hepatic CYP 2E1 activity was increased immediately followingm-xylene exposure (300 ppm). CYP 2B1 and CYP 1A2 activities were increased through day 2,all activities returning to control values 5 days postexposure. 1-NN treatment caused severerespiratory toxicity that was prevented by prior m-xylene exposure. Lactate dehydrogenase(LDH) and protein were increased in nasal lavage fluid (NLF) but gamma-glutamyl transferase(GGT) was unchanged. m-Xylene coexposure prevented or ameliorated the increases inLDH and protein but increased GGT. 1-NN-induced increases in bronchoalveolar lavage fluid(BALF) LDH and GGT were attenuated by m-xylene. 1-NN caused pronounced histopathologicalchanges in both respiratory and olfactory regions of the nasal mucosa. Lesions in both regionswere characterized by acute epithelial necrosis and exfoliation and suppurative exudate in theairways. These changes were prevented by m-xylene coexposure. Serum aspartate aminotransferase(AST) and alanine aminotransferase (ALT) levels were not changed in animals exposed to1-NN but were increased by m-xylene coexposure. Low-level m-xylene exposure organ-selectivelyaltered CYP450 isozyme activities and subsequent 1-NN toxicity.