Inhibition of respiratory burst activity in alveolar macrophages by bisbenzylisoquinoline alkaloids: characterization of drug-cell interaction.
Ma-JY; Barger-MW; Ma-JK; Castranova-V
Exp Lung Res 1992 Nov; 18(6):829-843
The drug/cell interaction between alveolar macrophages and bisbenzylisoquinoline (BBIQ) alkaloids was researched through the monitoring of respiratory activity in macrophages isolated from male Sprague-Dawley-rats. Various BBIQ alkaloids were selected for their wide range of antifibrotic activity. Oxygen consumption and ATP concentration were measured in both resting and stimulated cells. Several alkaloids exhibited significant inhibition of the macrophages. With stimulants present, tetrandrine (TT) and fangchinoline (FA) were both very effective inhibitors, FA the most effective binder. Tubocurarine was the least effective inhibitor and binder. Since these alkaloids did not affect resting oxygen consumption, inhibition was not due to decreased cellular activity. Most alkaloids bound to the macrophages in a time dependent manner, with the rate of binding highest during the first 5 minutes. TT did not bind to dead or lysed cells, which suggested not only that cell integrity was essential to binding, but that binding was specific. Cytoskeleton modifiers blocked TT binding by 33 to 93%, implicating the importance of the integrity of the cytoskeleton to binding. The addition of BBIQ alkaloids to the cell medium had no effect on ATP content; therefore, inhibition was not due to ATP depletion. The drug concentration outside the cells decreased by 88 to 92%, portions much too high if endocytosis were at work. Also, the alkaloids not only had rapid half times and low activation energies, but drug cell interaction depended on cell viability and the integrity of the cytoskeleton. Considering these facts, as well as the poor correlation between lipophilicity and inhibitory potency, the authors conclude that BBIQ alkaloids bind specifically to alveolar macrophages in the rat.
NIOSH-Author; Alveolar-cells; Cellular-respiration; Cell-metabolism; Laboratory-animals; Cytology; Adenosines; Plasma-membrane
Dr. Jane Y. C. Ma, Biochemistry Section, NIOSH, 944 Chestnut Ridge Road, MS 204, Morgantown, WV 26505
Experimental Lung Research