Modification of pulmonary CYP2B1 and induced CYP1A1 activities by intravenous injection of iron dextran.
Ghanem-MM; Battelli-L; Barger-M; Nath-J; Hubbs-AF
Toxicologist 2005 Mar; 84(Suppl 1):72-73
Cytochrome P450s (CYPs) are membrane-bound heme-containing proteins (hemeproteins) that catalyze oxidation of xenobiotics producing less lipophilic substances thereby facilitating their excretion. The heme moiety of this protein is iron protoporphyrin IX, which plays the major role in the catalytic activity of the enzyme. We hypothesized that the bioavailability of iron modifies the activity of inducible (CYP1A1) and constitutional (CYP2B1) CYP isozymes in rat lungs. Therefore, male Sprague-Dawley rats were injected i.v. with 50 or 200 mg/kg BW iron as iron dextran. Saline was injected as a control. Eleven days later, rats were injected intraperitoneally with the classic CYP1A1 inducer, beta-naphthoflavone (BNF; 50 mg/kg BW), to induce CYP1A1. Three days after BNF injection, rats were sacrificed and the lungs were perfused by phosphate buffer saline (PBS) through the pulmonary artery to remove blood. Immediately after washing, the microsomes of the right lung lobes were freshly prepared to measure the CYP1A1-dependant enzymatic activity [ethoxyresorufin-O-deethylase (EROD)] and the CYP2B1-dependent enzymatic activity [pentoxyresorufin-O-deethylase (PROD)]. Before separation of microsomes by differential centrifugation, an equal portion of lung homogenate was freeze dried for measurement of lung iron. The results showed that pulmonary iron concentration was increased in rats receiving 50 mg/kg (310 + 31.45 µg/gm) and 200 mg/kg (796 + 37.8 µg/gm) iron compared to control (180 + 13.33 µg/gm). The activities of PROD and induced EROD were significantly decreased by injection of 200 mg/kg iron. These findings suggest that increasing rat lung iron content modifies xenobiotic metabolism in lung by decreasing the activity of CYP2B1 and inducible CYP1A1.
Proteins; Oxidation; Laboratory-animals; Animals; Animal-studies; Lung-disorders; Pulmonary-system-disorders; Respiratory-system-disorders
The Toxicologist. Society of Toxicology 44th Annual Meeting and ToxExpo, March 6-10, 2005, New Orleans, Louisiana