Inhibition of rat respiratory-tract cytochrome P-450 activity after acute low-level m-xylene inhalation: role in 1-nitronaphthalene toxicity.
The xylenes are commonly used industrial solvents that have been shown to inhibit cytochrome P-450 (CYP450) activities in an organ- and isozyme-specific pattern. This study examined the dose-response and durational effects of m-xylene inhalation on cytochrome P-450 activities in the respiratory tract and liver as well as the effects of these CYP450 alterations on 1-nitronaphthalene (1-NN)-induced respiratory or hepatic toxicity. After m-xylene inhalation exposure 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 activities of these CYPs returned to those of control by day 2 but lung CYP 2B1 was increased 5 days following m-xylene exposure. Hepatic CYP 2E1 activity was increased immediately following m-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 severe respiratory 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 in LDH 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 histopathological changes in both respiratory and olfactory regions of the nasal mucosa. Lesions in both regions were characterized by acute epithelial necrosis and exfoliation and suppurative exudate in the airways. These changes were prevented by m-xylene coexposure. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were not changed in animals exposed to 1-NN but were increased by m-xylene coexposure. Low-level m-xylene exposure organ-selectively altered CYP450 isozyme activities and subsequent 1-NN toxicity.
Foy
Jeffrey W-D
JW
Toxicology Program, Northeastern University, Boston, Massachusetts 02115, USA.
Schatz
Robert A
RA
D000280:Administration, Inhalation; D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity*; D009297:Nasal Mucosa / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects* / Q000201:enzymology; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D014992:Xylenes / Q000008:administration & dosage / Q000633:toxicity*; D005723:gamma-Glutamyltransferase / Q000097:blood
D065607:Cytochrome P-450 Enzyme Inhibitors; D009281:Naphthalenes; D012997:Solvents; D014992:Xylenes; D003577:Cytochrome P-450 Enzyme System; C016614:1-nitronaphthalene; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; C031285:3-xylene