Prediction of pulmonary benzo(a)pyrene 4,5-oxide clearance: a pharmacokinetic analysis of epoxide-metabolizing enzymes in rabbit lung.
Extrapolation of in vitro data to predict occurrences in vivo is an uncertain process at best. In this study, clearance concepts initially developed to describe elimination of drugs and other substances by kidney and liver have been extended to calculate pulmonary extraction of circulating benzo(a)pyrene 4,5-oxide. Apparent kinetic parameters (Km and Vmax) for pulmonary microsomal epoxide hydrolase and cytosolic glutathione S-transferase were estimated by using in vitro enzyme assays, and whole tissue Vmax values of the two epoxide-metabolizing pathways were determined. From these data, a whole organ extraction ratio for benzo(a)pyrene 4,5-oxide was derived. The calculated extraction ratio (nearly one) was greater than, but in reasonable agreement with, the measured extraction ratio determined by using isolated perfused rabbit lungs exposed to circulating benzo(a)pyrene 4,5-oxide. The actual extraction ratio was 0.64 +/- 0.04 (x +/- S.D.,N = 3), which indicated that the rabbit lung was capable of removing a large percentage of circulating benzo(a)pyrene 4,5-oxide in a single pass through the organ. Therefore, the lung may play an important role in removing and biotransforming circulating arene oxides, as the entire cardiac output passes through the pulmonary capillary bed.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism*; D001711:Biotransformation; D003600:Cytosol / Q000378:metabolism; D004851:Epoxide Hydrolases / Q000378:metabolism; D004852:Epoxy Compounds / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011817:Rabbits
D001580:Benzopyrenes; D004852:Epoxy Compounds; D004988:Ethers, Cyclic; C006707:benzo(a)pyrene 4,5-epoxide; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases