Mineral Dusts Oxidize Methionine Residues: Probable Mechanism of Inactivation of Alpha-1-Antitrypsin

Abstract

There is now extensive evidence that mineral dusts induce airflow obstruction, and that exposure to some types of mineral dust, especially coal and silica, is associated with the presence of radiologic and pathologic emphysema (Becklake, 1989; Oxman et al., 1993; Leigh et al., 1983; Cockroft et al, 1982; Ruckley et al., 1984). However, little is known of the mechanism of emphysema induction by mineral particles. Because many mineral dusts can catalyse the formation of active oxygen species (AOS) in aqueous solution (Pezerat et al., 1989; Fubini et al., 1995) and because all mineral dusts evoke an inflammatory reaction in the lung, we postulated that mineral particles may induce emphysema by mechanisms similar to those thought to apply cigarette smoke; namely, excess release of proteolytic enzymes from dust-evoked inflammatory cells with subsequent breakdown of alveolar wall connective tissue and oxidative inactivation of alAT, the major anti-proteolytic protein in the lung, by dust-catalysed active ozygen species (Evans and Pry or, 1992), as well as by AOS released from dust-evoked inflammatory cells. We have previously shown that intratracheal instillation of mineral dusts does result in increased levels of desmosine, a measure of elastin breakdown and hydroxyproline, a measure of collagen breakdown, in lavage fluid (Li et al., 1996) and also that exposure of purified alAT to crystalline silica results in loss of antiproteolytic activity through a hydrogen peroxide mediated mechanism (Zay et al., 1995). It is believed that cigarette smoke inactivates alAT by oxidizing methionine residues (Carp et al., 1982), although few reports of this phenomenon have been published. We now extend our observations by testing whether mineral dusts can similarly oxidize methionine, either as a pure amino acid, or in whole proteins.