Effect of bleomycin-induced fibrosis on pulmonary metabolism of selected xenobiotics.

Few studies are available characterizing the effects of fibrosis on pulmonary disposition of drugs or environmental pollutants. Two model substrates, p-nitroanisole and carbofuran, were selected to evaluate the effect of bleomycin-induced fibrosis on pulmonary disposition and metabolism using the isolated perfused lung and in vitro enzyme preparations. The rate of p-nitroanisole oxidation in the isolated perfused lung was significantly lower in fibrotic (k = 0.0334 min-1) than in control (k = 0.0493 min-1) lungs. However, there was no difference in the amount of p-nitrophenol formed between control (38 +/- 4 micrograms) and fibrotic (47 +/- 7 micrograms) lungs. Carbofuran clearance was similar in control (t1/2 = 91 min, ke = 0.008 min-1) and fibrotic (t1/2 = 75 min, ke = 0.009 min-1) lungs and was consistent with a one-compartment model. The Km value for p-nitrophenol formation in microsomes (0.185 +/- 0.095 mM) from control lungs was similar to fibrotic lungs (0.054 +/- 0.014 mM); however, Vmax was significantly higher in healthy (34.6 +/- 6.3 pmoles/min per mg microsomal protein) than in fibrotic (11.16 +/- 3.19 pmoles/min per mg microsomal protein) lungs. In vitro carbofuran studies indicated limited metabolism of carbofuran in both healthy and fibrotic microsomal enzyme preparations (< 5% of the administered dose). Lower p-nitroanisole metabolism in fibrotic lungs was consistent with lower levels of cytochrome P-450 2B1/B2 measured in bleomycin-treated lungs. Results suggest that individuals with bleomycin-induced pulmonary fibrosis may be at greater risk when exposed to certain toxic environmental chemicals or drugs that require detoxification by pulmonary microsomal enzymes.