Seubert John M, Sinal Christopher J, Bend John R
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada N6A 5C1.
J Biochem Mol Toxicol. 2002;16(2):84-95. doi: 10.1002/jbt.10022.
Modulation of the cytochrome P450 (CYP) monooxygenase system (P450) by arsenite was investigated in male, adult Sprague-Dawley rats treated with a single dose (75 micromol/kg, sc) of sodium arsenite (As3+). Total CYP content and P450-dependent 7-pentoxyresorufin O-pentylation (PROD) and 7-ethoxyresorufin O-deethylation (EROD) activities of liver microsomes decreased maximally (33, 35, and 50% of control, respectively) 1 day after As3+ treatment. Maximum decreases of CYP content and P450 catalytic activities corresponded with maximum increases of microsomal heme oxygenase (HO) activity and with increased total plasma bilirubin concentrations. EROD activity increased maximally in lung (300%) 5 days after a single dose of As3+. Lung CYP1A1 mRNA and protein levels also increased maximally 5 days after treatment. A small but significant increase in EROD activity (65%) was observed in lung microsomes 24 h following a 1 h infusion of bilirubin (7.5 mg/kg) into rats. However, administration of bilirubin to the lung via intratracheal injection (0.25 and 2.5 mg/kg) did not increase CYP1A1 monooxygenase activity or mRNA. This study demonstrates that P450 is modulated in an isozyme (CYP1A1 vs CYP2B1/2) selective manner in rat lung after acute As3+ administration. Administration of bilirubin, a potential aryl hydrocarbon receptor (AHR) ligand, by infusion or intratracheal instillation did not upregulate pulmonary CYP1A1 at the mRNA level under our treatment conditions.
