Superoxide production by the mycobacterial and pseudomonad quinoid pigments phthiocol and pyocyanine in human lung cells.
The quinoid pigments pthiocol, produced by Mycobacterium tuberculosis, and pyocyanine, produced by Pseudomonas aeruginosa, were examined for their effects on O2.- production in cultured human lung epithelial-like A549 cells. Intracellular O2.- levels were measured using the O2.-sensitive aconitase(s), and rates of O2.- generation were assessed from rates of antimycin-resistant respiration. Elevated O2.- was detected in cells exposed to < 25 microM phthiocol and < 2 microM pyocyanine in neutral pH medium, and both agents impaired cell growth. The O2.- scavenging manganoporphyrin, Mn(III)TMPyP, partially protected cells against pyocyanine and phthiocol-mediated growth inhibition. O2.- production by phthiocol and pyocyanine was enhanced by acidification of the growth medium. Surprisingly, the dicumarol-inhibitable quinoid detoxification enzyme DT-diaphorase was a significant source of phthiocol and pyocyanine-mediated O2.- generation in cells. O2.- production in macrophages by the phthiocol analog, menadione, was shown to impair macrophage mitochondrial respiration and bactericidal activity toward Escherichia coli. Phthiocol and pyocyanine, by producing O2.-/H2O2, and inhibiting host cell aconitase activity, energetics, and other host cell functions, may contribute to the pathogenicity of M. tuberculosis and P. aeruginosa.
Gardner
P R
PR
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
D000154:Aconitate Hydratase / Q000378:metabolism; D000968:Antimycin A / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D001728:Dicumarol / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008168:Lung; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008665:Metalloporphyrins / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000737:chemistry; D009285:Naphthoquinones / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010860:Pigments, Biological / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D011710:Pyocyanine / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D014812:Vitamin K / Q000494:pharmacology
D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D009285:Naphthoquinones; D010860:Pigments, Biological; D013481:Superoxides; D014812:Vitamin K; D000968:Antimycin A; C050950:tetrakis(N-methyl-4-pyridiniumyl)porphine manganese(III) complex; D001728:Dicumarol; C008902:phthiocol; D011710:Pyocyanine; D000154:Aconitate Hydratase