Enhanced hepatic expression of P450IIE1 following inhalation exposure to pyridine.
Previous research has shown that intraperitoneal injection of the solvent pyridine results in a dose- and time-dependent induction of hepatic P450IIE1 in rats, with a twofold increase observed at 6 hr post-treatment. However, inhalation is the primary route of exposure expected for humans exposed to pyridine in laboratory and industrial settings or in tobacco smoke. In view of the potency and rapidity of induction associated with pyridine treatment, research was initiated to examine whether inhalation of the solvent at the current threshold limit value level of 5 ppm or at an elevated level of 440 ppm resulted in sufficient nasal and pulmonary uptake and systemic redistribution to cause increased hepatic expression of rat cytochrome P450IIE1. Rats were exposed, 6 hr/day, to 5 ppm pyridine for 4 days; to 440 ppm pyridine for 1 or 4 days; or to filtered air for 1 or 4 days. Rats were sacrificed 18 hr after the last exposure. Liver samples were taken from the air- and pyridine-exposed rats. Expression of immunoreactive P450IIE1 was examined in tissue sections using immunohistochemistry and in microsomal preparations using Western blot analyses. Hepatic tissue obtained from rats exposed to 5 ppm pyridine for 4 days or to 440 ppm pyridine for 1 or 4 days displayed significantly elevated levels of immunoreactive P450IIE1. Immunohistochemical analyses of liver sections showed that inhalation of pyridine at 5 ppm resulted in an elevated expression of P450IIE1 in hepatocytes surrounding terminal hepatic venules (THVs). Exposure to 440 ppm pyridine caused both increased expression of IIE1 in hepatocytes surrounding THVs after a single 6-hr exposure and an approximately three- to fourfold increase in the total number of cells expressing IIE1 after 4 days of exposure. Dilution analysis of immunohistochemically stained tissue revealed a significant difference between air-exposed controls and pyridine-exposed rats, at all exposure levels. P450IIE1 levels in microsomes isolated from rats receiving 5 and 440 ppm pyridine for 4 days were increased 2.5- and 10-fold as judged from scanning laser densitometry. This study reveals that inhalation of pyridine vapors at levels equal to or greater than the current threshold limit value of 5 ppm results in significant hepatic induction of P450IIE1 in rats.
Hotchkiss
J A
JA
Inhalation Toxicology Research Institute, Lovelace Biomedical Environmental Research Institute, Albuquerque, New Mexico 87185.
Kim
S G
SG
Novak
R F
RF
Dahl
A R
AR
D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D019392:Cytochrome P-450 CYP2E1; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007150:Immunohistochemistry; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D011725:Pyridines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D011725:Pyridines; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C023666:pyridine