Pharmacokinetic investigation of the fate of particle adsorbed polycyclic aromatic hydrocarbons in the isolated, perfused and ventilated rat lung. I. DNA binding, dose-dependent metabolism, and bioavailability, using benzo( a)pyrene as the model compound

Abstract

Benzo( a)pyrene [B(a)P] was administered intratracheally to the isolated, perfused, and ventilated rat lung as a model compound for urban air polycyclic aromatic hydrocarbons. The compound was given in two forms, adsorbed onto urban air particles (UAP) and as microcrystals (MCr). The appearance of unmetabolized B(a)P in the perfusion buffer differed significantly between the dosage forms, UAP releasing B(a)P with an apparent first-order rate constant of 0.007 ± 0.002 min −1 and the MCr preparation, correspondingly by 0.051 ± 0.030 min −1. The elimination of circulating B(a)P, administered directly to the buffer, was observed to be readily described by the classical two compartment model: C = 245 × e −0.050x t − 14 × e −0.010x t pmol/mL. The production of polar metabolites, released to the perfusate at 150 min, was about five fold higher for B(a)P administered as MCr compared to UAP preparations, at 1.5-μg doses. At 100-μg doses, there was only a two fold difference in the metabolite production, indicating an enzyme saturation at high dose levels. The metabolite pattern was affected by UAP adsorption of B(a)P, producing a relative increase in the formation of B(a)P-9,10-dihydrodiol, whereas the phenol formation was decreased. The covalent binding of reactive metabolites to DNA also differed significantly between groups. Normalizing the total binding, to the metabolite production, the UAP-adsorbed B(a)P produced DNA adducts more efficiently than the MCr preparation; 2.62 (±0.59) × 10 −5 versus 1.33 (±0.21) × 10 −5 pmol metabolites bound per mg DNA and per total amount, pmol, metabolites formed. Results indicate a possible mechanism for the co-carcinogenic action of exposure for B(a)P and a carrier particle by an increased pulmonary retention and/or altered metabolite patterns enhancing the formation of reactive and DNA damaging metabolites.