A selective decrease in the xenobiotic metabolizing activity of rat lungs by nitrogen dioxide exposures.
Groups of male Wistar rats were continuously exposed to nitrogen dioxide (NO2) ranging from 1.2 to 15 ppm for 1 or 2 weeks to examine the dose-effect relationship between NO2 and the xenobiotic metabolizing activity of lung microsomes. The lung cytochrome P-450 decreased significantly after 1-week exposures to 10 and 15 ppm NO2 and showed a decreasing tendency after 2-week exposures to 6-10 ppm NO2. On the other hand, the cytochrome b5, NADPH-cytochrome P-450 reductase and NADH-cytochrome b5 reductase of lung microsomes were increased concomitant with increase in microsomal proteins during 2-week exposures to 6-10 ppm NO2. These results show that the lung cytochrome P-450 decreases preferentially upon exposure to NO2 at higher concentrations. The coumarin hydroxylase activity was the most sensitive to NO2 exposures among activities metabolizing 4 kinds of xenobiotics examined. The coumarin hydroxylase activity was decreased in a dose-dependent fashion to 67-10% of the control level by 2-week exposures to 1.2-6 ppm NO2 and became negligible at 10 ppm NO2. The 7-ethoxycoumarin O-deethylase activity was also decreased to 82-56% of the control level by 2-week exposures to 1.2-6 ppm NO2 and became a constantly reduced level at 10 ppm NO2. The benzo[a]pyrene hydroxylase activity was decreased by exposures to NO2 above 10 ppm, and the benzphetamine N-demethylase activity also decreased during 2-week exposures to 6-10 ppm NO2. These results indicate that exposures to NO2 above 1.2 ppm cause a consistent and preferential reduction in the activities of coumarin hydroxylase and 7-ethoxycoumarin O-deethylase of lung microsomes in a dose-dependent manner.
Takahashi
Y
Y
Basic Medical Sciences Division, National Institute for Environmental Studies, Ibaraki, Japan.
Miura
T
T
D015660:7-Alkoxycoumarin O-Dealkylase; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D003579:Cytochrome Reductases / Q000378:metabolism; D042966:Cytochrome-B(5) Reductase; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D004790:Enzyme Induction / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000633:toxicity*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D010105:Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains
D000393:Air Pollutants; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010105:Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; D001579:Benzopyrene Hydroxylase; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; D003579:Cytochrome Reductases; D042966:Cytochrome-B(5) Reductase; D009251:NADPH-Ferrihemoprotein Reductase; D009585:Nitrogen Dioxide