Genotoxic bioactivation of constituents of a diesel exhaust particle extract by the human lung.

The ability of the human lung to catalyze genotoxic bioactivation of constituents of diesel exhaust particle (DEP) extract (DEPE) and the identity of the lung enzymes involved in the bioactivation were investigated using human lung tissues obtained from surgical resections. Genotoxicity was determined by lung S9-catalyzed mutagenicity of DEPE constituents to Salmonella typhimurium TA98NR in the Ames test and by DEPE-induced pneumocyte DNA damage response as determined by γH2Ax expression in ex vivo tissues. S9 was prepared from lung explants treated ex vivo with either DEPE to induce pulmonary enzymes (DEPE-S9) or vehicle only (CON-S9). TA98NR served as the tester strain for the purpose of enhancing and minimizing the contribution of lung S9 and Salmonella, respectively, to DEPE bioactivation. DEPE-S9 was 2.2-fold more active than CON-S9 or rat liver S9 in DEPE bioactivation and the bioactivation was inhibited 58, 45, 22, and 16% by α-naphthoflavone, dicumarol, ketoconazole, and ticlopidine, respectively. Alveolar S9 was less active than bronchioalveolar S9 in DEPE bioactivation. DEPE and diesel exhaust particles (DEP) induced γ-pH2Ax expression in pulmonary cells. Pulmonary CYP1A1 and NQO1 were induced by DEPE treatment, with the constitutive and induced CYP1A1 distributed throughout all peripheral lung regions, whereas NQO1 was limited in distribution to bronchiolar epithelium. The results show that the human lung is highly active in catalyzing genotoxic bioactivation of diesel emission constituents and that CYP1A and NQO1 play major roles in the reaction. The findings underscore the usefulness of human lung tissues in studies of the pneumotoxicity potential of chemicals to humans.

Cytochromes P4501 (CYP1): catalytic activities and inducibility by diesel exhaust particle extract and benzo[a]pyrene in intact human lung ex vivo.

Catalytic activities of CYP1A1, CYP1A2 and CYP1B1, and inducibility of the activities were studied in intact human lung samples (from 23 human subjects) ex vivo. The activities [as measured by ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), and 3-cyano-7-ethoxycoumarin O-deethylase (CECOD)] were present in the lungs and were induced by benzo[a]pyrene (B[a]P) and diesel exhaust particle extract (DEE) but with extensive inter-subject variability. All three activities were substantially inhibited (>or=75%) by the CYP1 inhibitor alpha-naphthoflavone, whereas only MROD and CECOD were substantially inhibited by the CYP1A2-preferential inhibitor fluvoxamine. None of the three activities was substantially inhibited by the CYP1B1-preferential inhibitor tetramethoxystilbene, indicating lack of involvement of CYP1B1 in the activities in the intact lung. CYP1A1 and CYP1A2 proteins were present in the lungs (by western blot analysis), also with extensive inter-subject variability, and were induced by B[a]P or DEE more extensively than by the combination of B[a]P and DEE (B[a]P+DEE). CYP1B1 was also present in the lungs and its level varied extensively between subjects. In contrast with CYP1A and CYP1A2 levels, CYP1B1 level was not significantly altered by B[a]P or DEE treatment and was diminished more extensively by treatment with B[a]P+DEE. The findings point to the potential usefulness of the intact lung for assessing in situ xenobiotic biotransformation reactions as well as the CYP1 specificity of the reactions ex vivo. The findings also suggest MROD and CECOD as potential markers of CYP1A2 activity in the intact lung.

Resection of a thoracic duct lymphangioma using video-assisted thoracoscopic surgery.

Thoracic duct lymphangioma is a rare mediastinal tumor. Most patients are asymptomatic. Symptoms may include dysphagia, dyspnea, cough, or chest pain. Workup may include chest computed tomography or lymphangiography, or both. Surgery should be considered the treatment of choice. We present a 60-year-old man with a 2.4-cm mass in the retro-cardiac space to the right of the esophagus. The patient underwent a thoracoscopic resection of the mass with ligation of the thoracic duct. We conclude that video-assisted thoracoscopic surgery allows for safe evaluation and resection of mediastinal pathology.

Induction of CYP1A1 and CYP1A2 expressions by prototypic and atypical inducers in the human lung.

The inducibility of cytochrome P4501A1 gene (CYP1A1) expression was examined in human lung samples from 27 subjects, using an explant culture system and semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. CYP1A1 transcripts were present in all of the lung specimens and were induced by the prototypic inducers 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (B[a]P), and by the atypical inducers pyridine, nicotine, and omeprazole. 2-Hydroxypyridine was a better inducer than pyridine, implicating metabolites in CYP1A1 induction by the parent compound. The prototypical inducers were the most effective inducers in many samples but were ineffective in some samples in which the atypical compounds were effective inducers. Cytochrome P4501A2 (CYP1A2) transcripts were also detected in most of the lung specimens and were inducible in some specimens. The results show the suitability of the explant culture system for examining the inducibility of human pulmonary CYP1A1 and CYP1A2, indicate the heterogeneity in individual sensitivity to the induction, and underscore the need to include atypical inducers in studies of CYP1A inducibility in humans.