Influence of airborne particulate on the metabolism of benzo[a]pyrene in the isolated perfused lung

Abstract

Benzo[a]pyrene (BaP), a ubiquitous potent carcinogen, has been associated with the increased incidence of human bronchiogenic carcinoma in occupational and urban settings. A detailed knowledge of the rate and pattern of metabolite formation and factors affecting their formation is essential for understanding the mechanism of action of BaP in the lung. An isolated perfused New Zealand rabbit lung preparation was used to investigate the effects of a crude airborne particuiate mixture on the metabolism of BaP. [¹⁴C]BaP with and without crude air particuiate (CAP) was administered intratracheally to an isolated perfused lung (IPL) preparation after intratracheal pretreatment of the whole animal with CAP and/or BaP, or intra‐peritoneal pretreatment of the whole animal with BaP. BaP and its metabolites were extracted from perfusing blood at 6 time points up to 180 min after administration of [¹⁴C/BaP to the IPL. BaP and its metabolites were also extracted from lung tissue, washout fluid, aveolar macrophages, and trachea bronchi at the end of the perfusion at 180 min. Patterns of BaP metabolites were determined by chromatographic techniques and liquid scintillation counting.

Particuiate pretreatment of the whole animal or administration of the particuiate to the IPL altered BaP metabolism by the perfusing lung. Particuiate pretreatment of the whole animal resulted in increases in the total rates of appearance of metabolites of BaP in the blood (ng/g lung·h), while particuiate administration to the IPL resulted in decreases in the total rate of appearance of metabolites of BaP in the blood and negated the effects of pretreatments. Coadministration of particuiate with BaP to the IPL with and without particuiate pretreatment of the whole animal, or BaP administration to the IPL preceded by particuiate pretreatment of the whole animal, enhanced dihydrodiol formation and depressed formation of water‐soluble materials. This is important because dihydrodiol formation is considered part of the active pathway of BaP carcinogenicity. These data suggest that pulmonary particuiate exposure in the presence of BaP results in the initial increased production of dihydrodiois of BaP that may be further metabolized to compounds believed to be the ultimate carcinogenic form(s) of BaP.