title: Effects of induction and age-dependent enzyme expression on lung bioavailability, metabolism, and DNA binding of urban air particulate-absorbed benzo[a]pyrene, 2-nitrofluorene, and 3-amino-1,4-dimethyl-5H-pyridol-(4,3)-indole.
abstract: The effect of interactions between urban air particulates (UAP) and carcinogens on bioavailability, metabolism, and DNA binding was studied in the isolated perfused and ventilated rat lung. The availability of benzo[a]pyrene (B[a]P) varied from 29 to 60% after intratracheal doses of carcinogen particulates dissolving extremely slow and fast, respectively. Several cytochrome P450 enzyme (P450) inducers acting as 2,3,7,8-tetrachlorodibenzo[p]dioxin-receptor ligands have been identified in UAP extracts. beta-Naphthoflavone (BNF) was used to study how P450 induction alters the lung metabolism of carcinogens. Pretreatment increased the lung clearance for B[a]P 8-fold and for 2-nitrofluorene (2NF) by a factor of four from 0.55 +/- 0.06 ml/min to 2.37 +/- 0.62 ml/min. Studies with the intact lung and with isolated lung cells show that carcinogen metabolism and pharmacokinetics depend both on the route of exposure and dosage and on the distribution of specific enzymes. A cytochrome P450IIB1 enzyme was detected in lung epithelial cells where it catalyzes 9-hydroxylation of 2NF. This rat lung 2NF-9-hydroxylation capacity increases in parallel with the age dependent up-regulation of lung P450IIB1 expression. Both human and rat lung tissue have the capacity to form 9-hydroxy-2-nitrofluorene (9-OH-2NF) that is mutagenic. A BNF-inducible P450IA1 was detected in endothelial and alveolar type II cells. Consequently, aromatic hydroxylation dominated when 2NF was dosed directly into the lung circulation. Pretreatment of rats with BNF before intratracheal B[a]P dosage induced lung cytochrome P450IA1. The 7,8-dihydroxy-9,10-oxybenzo[a]pyrene-deoxyguanosine adduct and the total lung DNA adduct levels increased significantly from a peak level of 75 +/- 8 to 151 +/- 19 fmole/mg DNA in lungs from control and BNF pretreated rats, respectively. 3-Amino-1,4-dimethyl-5H-pyridol-(4,3)-indole (TRP-P1) is a potent mutagen and carcinogen identified in UAP extracts. Dietary BNF pretreatment of rats altered the [14C]TRP-P1 distribution as analyzed by whole-body autoradiography. An enhanced retention was observed in the small intestine, forestomach, esophagus, and lung. UAP catalyzes oxygen radical formation and deoxyguanosine-8-hydroxylation, which were inhibited when the UAP samples were extracted with organic solvents or when they were incubated in the presence of desferroxamine. We therefore postulate that a polycyclic aromatic hydrocarbon autooxidation pathway may be responsible for generation of hydrogen peroxide, which may be further converted to hydroxyl radicals through an iron-dependent reaction.
authors: Department of Oncology and Clinical Pharmacology, Umeå University Hospital, Sweden.
authors: J P
authors: JP
authors: Gøtze
authors: P
authors: P
authors: Lindeskog
authors: C S
authors: CS
authors: Törnquist
mesh_terms: D000375:Aging / Q000378:metabolism; D000393:Air Pollutants / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000494:pharmacology; D001682:Biological Availability; D002243:Carbolines / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts; D004790:Enzyme Induction; D005434:Flow Cytometry; D005449:Fluorenes / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007442:Intubation, Intratracheal; D008168:Lung / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000393:Air Pollutants; D002243:Carbolines; D018736:DNA Adducts; D005449:Fluorenes; C019499:2-nitrofluorene; D001564:Benzo(a)pyrene; C019132:3-amino-1,4-dimethyl-5H-pyrido(4,3-b)indole