title: 9,10-Phenanthrenequinone promotes secretion of pulmonary aldo-keto reductases with surfactant.
abstract: 9,10-Phenanthrenequinone (9,10-PQ), a major quinone in diesel exhaust particles, induces apoptosis via the generation of reactive oxygen species (ROS) because of 9,10-PQ redox cycling. We have found that intratracheal infusion of 9,10-PQ facilitates the secretion of surfactant into rat alveolus. In the cultured rat lung, treatment with 9,10-PQ results in an increase in a lower-density surfactant by ROS generation through redox cycling of the quinone. The surfactant contains aldo-keto reductase (AKR) 1C15, which reduces 9,10-PQ and the enzyme level in the surfactant increases on treatment with 9,10-PQ suggesting an involvement of AKR1C15 in the redox cycling of the quinone. In six human cell types (A549, MKN45, Caco2, Hela, Molt4 and U937) only type II epithelial A549 cells secrete three human AKR1C subfamily members (AKR1C1, AKR1C2 and AKR1C3) with the surfactant into the medium; this secretion is highly increased by 9,10-PQ treatment. Using in vitro enzyme inhibition analysis, we have identified AKR1C3 as the most abundantly secreted AKR1C member. The AKR1C enzymes in the medium efficiently reduce 9,10-PQ and initiate its redox cycling accompanied by ROS production. The exposure of A549 cells to 9,10-PQ provokes viability loss, which is significantly protected by the addition of the AKR1C3 inhibitor and antioxidant enzyme and by the removal of the surfactants from the culture medium. Thus, the AKR1C enzymes secreted in pulmonary surfactants probably participate in the toxic mechanism triggered by 9,10-PQ.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. matsunagat@gifu-pu.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Mariko
authors.initials: M
authors.lastname: Haga
authors.forename: Gou
authors.initials: G
authors.lastname: Watanabe
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Yu
authors.initials: Y
authors.lastname: Kajiwara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Naoki
authors.initials: N
authors.lastname: Inagaki
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000551:Ambroxol / Q000494:pharmacology; D000818:Animals; D018938:Caco-2 Cells; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D008297:Male; D010616:Phenanthrenes / Q000494:pharmacology*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013501:Surface-Active Agents / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D010616:Phenanthrenes; D017382:Reactive Oxygen Species; D013501:Surface-Active Agents; D000551:Ambroxol; C005399:9,10-phenanthrenequinone; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase