title: In vitro protection by erdosteine against oxidative inactivation of alpha-1-antitrypsin by cigarette smoke.
abstract: Direct exposure in vitro of the protein alpha 1-antitrypsin (alpha 1-AT; human neutrophil elastase inhibitor, alpha 1-proteinase inhibitor) to gas phase cigarette smoke causes a loss of elastase-inhibitory capacity (EIC). This effect appears to be related to the formation of reactive oxygen species in the smoke that inactivate alpha 1-AT by oxidizing the methionine terminal amino acid. Reducing agents such as glutathione and ascorbic acid prevent this inactivation. In the present investigation erdosteine, a novel thiol derivative, which contains two blocked SH groups with potential reducing properties, was tested in vitro for its capacity to protect human alpha 1-AT. For the purpose, the compound, previously hydrolyzed with bicarbonate-carbonate buffer or with microsomal enzymes was put in contact with alpha 1-AT and exposed to gas phase cigarette smoke. The EIC of alpha 1-AT was then measured by incubating the samples with leukocyte elastase and, subsequently, by titrating the residual elastolytic activity against a synthetic substrate. Under these conditions erdosteine effectively protected alpha 1-AT against the smoke injury and, after alkaline hydrolysis, it appeared to be as active as glutathione and ascorbic acid (EC50 being respectively 6.4, 7.2 and 6.2 mM). This evidence suggests that the erdosteine SH groups, which can become free, may have an important role in the mechanism of action, by blocking highly reactive oxygen-free radicals. Erdosteine may have a therapeutic application in preventing oxidative lung damage induced by cigarette smoke.
authors: Department of Pharmaceutical Chemistry, University of Pavia, Italy.
authors: G
authors: G
authors: Gazzani
authors: G B
authors: GB
authors: Fregnan
authors: G
authors: G
authors: Vandoni
mesh_terms: D001205:Ascorbic Acid / Q000494:pharmacology; D005609:Free Radicals; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010947:Plants, Toxic; D012906:Smoke; D013864:Thioglycolates / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D014026:Nicotiana; D000515:alpha 1-Antitrypsin
chemical_list: D005609:Free Radicals; D012906:Smoke; D013864:Thioglycolates; D013876:Thiophenes; D000515:alpha 1-Antitrypsin; C048498:erdosteine; D005978:Glutathione; D001205:Ascorbic Acid