© 1990 Oxford University Press
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2-Nitrofluorene metabolism in rat lung. Pharmacokinetic and metabolic effects of ß-naphthoflavone treatment
1Department of Clinical Pharmacology and Hospital Pharmacy, The University Hospital S-901 85 Umeå
2Department of Medical Nuthtion, The Karolinska Institute at Huddinge University Hospital Novum F60, S-141 86 Huddinge
3Department of Biopharmaceutics and Pharmacokinetics, The Biomedical Center Box 580, Uppsala University, S-751 23, Uppsala
4Center for BioTechnology, Novum, Thc Karolinska Institute at Huddinge University Hospital S-141 52 Huddinge, Sweden
Absorption, metabolism and DNA binding of 2-nitrofluorene (NF) was studied in isolated, perfused and ventilated rat lungs and in lung microsomal incubations. Comparisons were made between control animals and animals treated with ß-naphtho-flavone (BNF), a 2,3,7,8-tetrachlorodibenzo(p)dixon (TCDD) receptor ligand and inducer of cytochrome P450IA1. Clearance of NF increased significantly in the isolated, perfused and ventilated lungs after BNF dosage, from 0.55 ± 0.06 ml/min to 2.37 ± 0.62 ml/min (P < 0.05, n=5–6). As a consequence of this, the mean residence time (MRT) for NF decreased when NF was dosed directly to the perfusion buffer, from 213 ± 23 min (n=6) to 48 ± 9 min (n=6), and after intratracheal dosage from 289 ± 101 min (n=5) to 135 ± 72 min (n=5). Irreversible binding of NF metabolites to DNA increased 2-fold after treatment with BNF when NF was dosed to the lung perfusion buffer. Treatment with BNF increased the rate of lung microsomal NF metabolism significantly, from 54 ± 5 to 106 ± 11 pmol/min/mg protein (P < 0.05, n=6–12). Formation of the monohydroxylated metabolite X-OHNF was inhibited in vitro by addition of 
-naphthoflavone (50 µM), by 89 and 98% with lung microsomal fractions from control and BNF-treated rats respectively. In contrast, proadifen (50 µM) preferentially inhibited formation of 9-OHNF, by 42 and 33% in incuba tions with lung microsomal fractions from control and BNF-treated animals. Anti-P450IIB1-IgG inhibited fonnatlon of 9-OHNF by 96 and 45% with lung microsomes from control and BNF-treated rats respectively. Formation of X-OHNF was unaffected by addition of anti-P-450IIB1-IgG in both cases. These results show that both constitutive and inducible microsomal rat lung enzymes metabolize NF. A constitutive enzyme, most likely cytochrome P450IIB1, catalyzes metabolic attack on NF with high preference for the 9-position. A BNF-inducible microsomal enzyme, most likely cytochrome P450IA1, catalyzes hydroxylation of NF both in the 9-position and in other positions. Increased metabolic clearance, metabolism and DNA binding of NF after BNF treatment suggest that the level and speficity of cytochrome P450 isozymes may be important determinants for toxicity and availability of NF in the rat lung.