The effects of a cocarcinogen, ferric oxide, on the metabolism of benzo[a]pyrene in the isolated perfused lung

Abstract

An isolated perfused New Zealand rabbit lung preparation was used to investigate the effects of a cocarcinogen, ferric oxide (Fe2O3), on the metabolism of benzo[a]pyrene (BaP), a ubiquitous potent carcinogen that has been associated with the increased incidence of human bronchiogenic carcinoma in occupational and urban settings. [14C]-BaP was administered intratracheally to an isolated perfused lung (IPL) preparation with and without Fe2O3 after intraperitoneal pretreatment of the whole animal with BaP or intratracheal pretreatment of the whole animal with Fe2O3 and/or BaP. BaP and its metabolites were isolated from serial blood samples up to 180 min after administration of [14C]BaP to the IPL. BaP and its metabolites were also isolated from lung tissue, washout fluid, macrophage, 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. Fe2O3 pretreatment to the whole animal or administration of Fe2O3 to the IPL altered BaP metabolism by the perfused lung. Fe2O3 pretreatment to the whole animal resulted in an increase in the total rate of appearance of metabolites of BaP in the blood (ng/g lung X h), while Fe2O3 administration to the IPL resulted in a decrease in the total rate of appearance of BaP metabolites in the blood and inhibited the effect of pretreatment. Administration of Fe2O3 with BaP to the IPL with or without Fe2O3 pretreatment to the whole animal, or BaP administration to the IPL preceded by Fe2O3 pretreatment to the whole animal, enhanced dihydrodiol formation and depressed formation of water-soluble metabolites. Since dihydrodiol formation is considered to be the active pathway of BaP metabolism, these data suggest that pulmonary exposure to a known cocarcinogen, Fe2O3, in the presence of BaP results in increased production of dihydrodiols of BaP, which may be further metabolized to the ultimate carcinogenic form(s) of BaP. Therefore, Fe2O3 can enhance the metabolic activation of BaP by the lung, as well as act as a carrier for penetration and retention of BaP in the lung.

Blood levels of polycyclic aromatic hydrocarbons in children and their association with oxidative stress indices: An Indian perspective

“…carcinogenesis [55]. Previous study indicated that high exposure is associated with an increased levels of aromatic adducts in PAHs exposed population [56] and suggested that alterations of PAH metabolism may play a crucial role in long-term particle-associated lung diseases and injuries induced by free radicals (FR), which are generated during its metabolism [57]. Oxidative stress and disturbed antioxidant status are well established in previously published studies of many childhood diseases [58,59].…”

Influence of iron (56Fe2O3 or 54Fe2O3) in the upregulation of cytochrome P4501A1 by benzo[a]pyrene in the respiratory tract of Sprague‐Dawley rats

“…We also showed that in vivo short-term exposure to BaP coated onto Fe 2 O 3 particles induced more pronounced proteinase/antiproteinase imbalance, oxidative stress conditions, inflammatory response and apoptosis than exposure to BaP alone (Garçon et al, 2000(Garçon et al, , 2001aGosset et al, 2003). Other authors have suggested that alteration of the metabolic activation of BaP may play a key role in long-term particle-associated lung disease (Warshawsky et al, 1984;Greife & Warshawsky, 1993;Cheu et al, 1997). Any influence of iron in PAH/iron oxide mixtures on the capacity of PAHs to induce metabolizing enzymes will be one of many ways in which iron oxides can affect PAH carcinogenicity (Vakharia et al, 2001a, b).…”

“…Indeed, Warshawsky et al (1984) attempted to stimulate the metabolic activation of BaP in lungs using an isolated perfused lung model in the presence of Fe 2 O 3 under different exposure conditions. They showed that exposure to Fe 2 O 3 in the presence of BaP led to increased production of adverse metabolites.…”