Inhibition of rat respiratory-tract cytochrome P-450 isozymes following inhalation of m-Xylene: possible role of metabolites.
Xylene is used as a solvent in paints, cleaning agents, and gasoline. Exposure occurs primarily by inhalation. The volatility and lipophilicity of the xylenes make the lung and nasal mucosa the primary target organs. m-Xylene (m-XYL) has been shown to alter cytochrome P-450 (CYP) activity in an organ- and isozyme-specific manner. The purpose of this work was to determine if the metabolism of m-XYL to the inhibitory metabolite m-tolualdehyde (m-ALD) is the cause of inhibition of CYP isozymes following in vivo inhalation exposure to m-XYL (100, 300 ppm), 3-methylbenzyl alcohol (3-MBA) (50, 100 ppm), or m-ALD (50, 100 ppm). A single 6-h inhalation exposure of rats to m-XYL inhibited pulmonary CYPs 2B1, 2E1, and 4B1 in a dose-dependent manner. Inhalation of 3-MBA inhibited pulmonary CYPs 2B1 and 4B1 in a dose-dependent manner. m-ALD inhibited pulmonary CYPs 2B1 and 2E1 in a dose-dependent manner, while 4B1 activity was increased dose dependently. Nasal mucosa CYP 2B1 and 2E1 activity was inhibited following exposure to m-XYL dose dependently, 3-MBA inhibited nasal mucosa CYPs 2E1 and 4B1 dose dependently. CYPs 2B1, 2E1, and 4B1 were inhibited in a dose-dependent fashion following inhalation of m-ALD. Following high-performance liquid chromatography (HPLC) analysis, m-ALD was detected after in vivo exposure to m-XYL, m-ALD, and 3-MBA in a dose-dependent manner, with highest m-ALD levels in the nasal mucosa and lung. Alteration of cytochrome P-450 activity by m-XYL could result in increased or decreased toxicity, changing the metabolic profiles of xenobiotics in coexposure scenarios in an organ-specific manner.
Vaidyanathan
Anu
A
Toxicology Program, Northeastern University, Boston, Massachusetts 02115, USA.
Foy
J W-D
JW
Schatz
Robert
R
D000818:Animals; D001547:Benzaldehydes / Q000008:administration & dosage / Q000633:toxicity; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D019570:Inhalation Exposure; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014992:Xylenes / Q000008:administration & dosage / Q000633:toxicity*
D001547:Benzaldehydes; D001592:Benzyl Alcohols; D007527:Isoenzymes; D014992:Xylenes; D003577:Cytochrome P-450 Enzyme System; C031285:3-xylene; C093383:3-methylbenzaldehyde; C042289:3-methylbenzyl alcohol