Andrew J. Ghio

Nitration of tyrosine by hydrogen peroxide and nitrite.

Peroxynitrite anion is a powerful oxidant which can initiate nitration and hydroxylation of aromatic rings. Peroxynitrite can be formed in several ways, e.g. from the reaction of nitric oxide with superoxide or from hydrogen peroxide and nitrite at acidic pH. We investigated pH dependent nitration and hydroxylation resulting from the reaction of hydrogen peroxide and nitrite to determine if this reaction proceeds at pH values which are known to occur in vivo. Nitration and hydroxylation products of tyrosine and salicyclic acid were separated with an HPLC column and measured using ultraviolet and electrochemical detectors. These studies revealed that this reaction favored hydroxylation between pH 2 and pH 4, while nitration was predominant between pH 5 and pH 6. Peroxynitrite is presumed to be an intermediate in this reaction as the hydroxylation and nitration profiles of authentic peroxynitrite showed similar pH dependence. These findings indicate that hydrogen peroxide and nitrite interact at hydrogen ion concentrations present under some physiologic conditions. This interaction can initiate nitration and hydroxylation of aromatic molecules such as tyrosine residues and may thereby contribute to the biochemical and toxic effects of the molecules.

Hypothesis: is lung disease after silicate inhalation caused by oxidant generation?

Inhaled silicate dusts may cause lung disease through their surface coordination of iron with subsequent oxidant generation via the Fenton reaction. Pneumoconiosis, irritant bronchitis, focal emphysema, and carcinoma may be produced by oxidants either directly through lipid peroxidation and protein inactivation, or indirectly by oxidant-mediated release of cytokines such as platelet-derived growth factor. The increased incidence of tuberculosis observed among silicate workers could be explained by accumulation of iron complexed by dust particles in the lung and made available to dormant mycobacteria as a virulence factor.

Generation of hydroxyl radical by crocidolite asbestos is proportional to surface [Fe3+]☆

Differences among fibrous silicates to effect injury in biological systems have been postulated to reflect oxidant generation by structural iron within the crystal lattice of amphiboles. Iron is also coordinated to the surface of all silicates in concentrations which depend on the density of acidic functional groups. We tested the hypothesis that oxidant generation by crocidolite is proportional to surface-complexed iron rather than variance in the lattice concentrations of this transition metal. Surface iron was quantified after its reduction to Fe2+ and chelation by citrate. Thiobarbituric acid (TBA) reactive products and dihydroxybenzoic acid products of salicylate were employed as indices of nonspecific oxidant and hydroxyl radical generation, respectively. Surface iron, TBA reactive products, and dihydroxybenzoic acid products all diminished after pretreatment of crocidolite with the metal chelator deferoxamine in concentrations varying from 0 to 250 mM. Inclusion of deferoxamine in the reaction mixture provided similar results of diminishing both TBA reactive products and dihydroxybenzoic acid generation. We conclude that oxidant generation by crocidolite is proportional to surface concentrations of iron which can be chelated using deferoxamine. The design of synthetic fibers without health effects after exposure will likely necessitate decreasing the number of surface acidic functional groups to diminish the capacity to complex iron (i.e., minimize the percentage SiO2).

Composition of Lung Lavage in Pulmonary Alveolar Microlithiasis

A case of pulmonary alveolar microlithiasis (PAM) is reported wherein total lung lavage was performed for relief of dyspnea. Characterization of the lavage material and examination of the microliths isolated from the lavage fluid confirmed previous reports of their spherical-ovoid shape and a 2:1 calcium to phosphate composition. The microliths contained considerable amounts of ionizable iron and generated oxidants in an in vitro system. A detailed biochemical analysis of the lavage fluid reflected elevations in total protein, phosphatidylserine, phosphatidylglycerol and the ratio of phosphatidylglycerol to phosphatidylinositol. Surfactant apoprotein-A levels approximated that of normal patients. The potential roles of oxidant generation and alterations in surfactant metabolism are discussed in the context of the pathogenesis of PAM.

Relative Intrinsic Potency of Asbestos and Erionite Fibers: Proposed Mechanism of Action

Data from human exposure to naturally occurring mineral fibers indicates extreme variability in the rate of mesothelioma between various asbestos varieties and erionite. Experiments on rats have confirmed these differences even where dose responses are based on the number, size and shape of the fibers. In vitro parameters of cytotoxicity and chromosomal aberrations follow the same trend. In such studies the zeolite fiber erionite, which possesses unique internal voids in the crystal lattice, ranks as several orders of magnitude more potent than any asbestos. The data suggests that an intrinsic physicochemical phenomenon is superimposed on the known length/width factor which is responsible for the variability in mesothelioma induction.

Erratum: The association between serum ferritin and uric acid in humans (Free Radical Research (2005) vol. 39 (337-342))

The Publisher and authors would like to draw attention to an error in the following article: Ghio AJ, Ford ES, Kennedy TP, Hoidal JR. The association between serum ferritin and uric acid in humans. Free Radic Res 2005;39:337 342. The regression coefficient for the total sample in Table II should be 0.0679. In addition, the authors wish to clarify that all R listed in Tables II V represent the model R from all variables in the models, not just ferritin. The conclusion that concentrations of ferritin are significantly and positively associated with concentrations of uric acid remains unchanged.