Lh. Pang et Jrs. Hoult, CYTOTOXICITY TO MACROPHAGES OF TETRANDRINE, AN ANTISILICOSIS ALKALOID, ACCOMPANIED BY AN OVERPRODUCTION OF PROSTAGLANDINS, Biochemical pharmacology, 53(6), 1997, pp. 773-782
Tetrandrine, an anti-inflammatory immunosuppressive bisbenzylisoquinol
ine alkaloid of Chinese herbal origin, is widely used to treat silicos
is and interferes with the regulation of calcium in many cell types. W
e investigated its effect on the cellular integrity of macrophages and
on their ability to generate prostaglandins and nitric oxide, mediato
rs of inflammation with immunomodulatory roles. Tetrandrine at 10(-7)
M to 10(-4) M caused dose- and time-dependent loss of cell viability o
f mouse peritoneal macrophages, guinea-pig alveolar macrophages and mo
use macrophage-like J774 cells. Loss of viability (50%) occurred withi
n 1-3 hr and required approximate to 5 x 10(-6) M tetrandrine. Loss of
macrophage viability after tetrandrine treatment was accompanied by t
he generation of large amounts of prostaglandin E(2) (PGE(2)), to leve
ls 285-877% of control. Coincubation with indomethacin abolished PGE(2
) generation, but did not prevent cell death. Tetrandrine did not caus
e generation of nitric oxide. Verapamil also reduced the viability of
mouse peritoneal macrophages and J774 cells, but did not cause PGE(2)
overproduction, except at 10(-4) M in mouse peritoneal macrophages. In
macrophages cultured with lipopolysaccharide and interferon-gamma to
induce the generation of large amounts of both PGE(2) and nitric oxide
, tetrandrine reduced mediator release and their forming enzymes (cycl
o-oxygenase-2 and inducible nitric oxide synthase), secondary to cytot
oxicity. The predominant action of tetrandrine is to exert a cytotoxic
effect on macrophages, perhaps by interfering with calcium homeostasi
s; this leads to overproduction of immunomodulatory but proinflammator
y prostaglandin. This may be relevant to its protective actions in hum
an fibrosing silicosis, in which there is alveolar macrophage involvem
ent. (C) 1997 Elsevier Science Inc.