RATES OF GLUTATHIONE SYNTHESIS IN LUNG SUBCOMPARTMENTS OF MICE AND MONKEYS - POSSIBLE ROLE IN SPECIES AND SITE-SELECTIVE INJURY

Injury to pulmonary epithelial cells from chemicals that undergo P45D- dependent metabolic activation and from gases such as ozone is highly focal. These studies examined the rates of glutathione resynthesis in pulmonary subcompartments (trachea, minor daughter/respiratory bronchi ole and parenchyma) of mice and monkeys to determine whether differenc es in glutathione synthesis are partly responsible for wide regional/ species variations in susceptibility of the lung to insult. Glutathion e levels remained unchanged in lung subcompartments incubated for up t o 4 hr in Waymouth's medium, Glutathione levels decreased less than 30 % in 4-hr incubations of monkey airways in medium devoid of sulfur ami no acids although in mouse airways decreases of 40 to 60% were observe d. Diethyl maleate depleted glutathione in lung subcompartments in vit ro by varying amounts depending on the species and subcomipartment exa mined. Airways incubated in the presence of cysteine but not methionin e or glutathione regenerated glutathione rapidly after diethyl maleate depletion. The rates of regeneration differed significantly with spec ies and airway level. In all airways of the monkey, glutathione levels returned to the initial level within 2 to 4 hr after addition of cyst eine containing medium although in mice recovery of glutathione requir ed only 1 (minor daughter and parenchyma) or 2 hr (trachea) incubation with cysteine supplemented medium. These studies show striking specie s and airway level differences in the rates of glutathione resynthesis and suggest that focal injury to respiratory epithelium may, in part, be mediated by regional differences in the ability to supply glutathi one for protection against electrophiles and reactive oxygen species.