Toxicity of platinum (IV) salts for cells of pulmonary origin.

Abstract

The acute toxicity of tetravalent platinum was studied in vitro by use of rabbit alveolar macrophages and human lung fibroblasts (strain WI-38). Alveolar macrophages were exposed in tissue culture for 20 hr to platinum dioxide (PtO2) or platinum tetrachloride (PtCl4). There was no evidence of dissolution of PtO2 and no decrease in viable cells at concentrations as high as 500 mug/ml. PtCl4 was soluble in the macrophage system and after a 20-hr exposure, resulted in loss of viability in 50% of the cells originally present at a concentration of 0.30mM (59 mug Pt/ml). After a 20-hr exposure, rapidly growing human lung fibroblasts were rendered nonviable by PtCl4 at comparable concentrations. A decrease in total cellular ATP was observed at lower concentrations in macrophages and fibroblasts along with a reduction in phagocytic activity of macrophages as compared to controls. With the fibroblasts, a 50% decrease in incorporation of 14C-thymidine was observed after a 22-hr exposure to PtCl4 at a concentration of 0.007mM; higher concentrations were required to inhibit the incorporation of 14C-uridine and 14C-leucine. Time-course studies indicated that the inhibition of 14C-thymidine incorporation was nearly complete (90%) after 7 hr in the presence of 0.06mM PtCl4. Under the same conditions, there was little inhibition (15%) of 14C-leucine incorporation and moderate inhibition (50%) of 14C-uridine incorporation. Higher concentrations of PtCl4 were required to inhibit 14C-thymidine incorporation into the acid-soluble fraction than were required to inhibit incorporation into the acid-precipitable fraction. Hence, the preferential inhibition of DNA synthesis by PtCl4 may result from an impairment of the incorporation process.

Tissue Organ Distribution and Behavioral Effects of Platinum Following Acute and Repeated Exposure of the Mouse to Platinum Sulfate

“…Since these correlations involved a number of tissues, but not the brain, a general systemic effect, rather than a neurotoxic effect, seems to be indicated. Pt compounds have been shown to inhibit DNA, RNA, and protein synthesis in vitro (25) and in vivo (1,21). Our findings suggest that Pt has a depressing effect on cellular processes and exposure to Pt above a threshold level results in general malaise which is manifested as a depression of certain behaviors.…”

Alterations in Macrophage Functions by Environmental Chemicals

“…On the contrary, vanadate (V03-) caused a 25% reduction in macrophage numbers and a loss in viability, but no effect was observed on the phagocytic index. Other in vitro studies with cigarette smoke (120-122), NO2 (123), CdO (124), Hg +, Cd2 , Zn2 , Pt4+, Cu2+, Ni2+, and V205 (73,125,126) have also shown a reduction in the phagocytic functioning of these defense cells.…”

“…The effects of exposure to NO2 (123,(145)(146)(147), 03 (138,141,(148)(149)(150), S02 (144,151,152), cigarette smoke (5,90,121,137,(153)(154)(155) silica (156), H2SO4 (132), Cd2+ (61,124), alumina (124), Ni2+ (117), Mn2+ (55,157), ethanol (158), PbCl2 (159), and high oxygen tensions (150) have all been investigated using model systems similar to the ones described above. Depressed bactericidal functions has been attributed to exposure to all of these substances except silica, SO2 and 02.…”

Effect of Platinum and Palladium Salts on Thymidine Incorporation into DNA of Rat Tissues

“…Waters et al (6) report that the incorporation of thymidine into DNA is more sensitive to inhibition by PtCl4 than the incorporation of uridine into RNA or of leucine into protein in cultured cells. The inhibition by PtCl4 may be analogous to the effect of Pt-containing antitumor compounds (7)(8)(9).…”