Effects of some chelating agents on bismuth absorption in the rat

Abstract

Bismuth encephalopathies appeared in the mid-seventies in France and concerned about 1,000 people and led to a fatal outcome in 70 cases. Responsibility of Bi was clearly confirmed by the disappearance of the intoxication after prescription of drugs containing Bi had been more tightly regulated. Since the implication of a substance increasing the intestinal absorption of Bi has been suspected, we studied the concentrations of Bi in the tissues of rats who had been treated with bismuth nitrate basic 400 mg/kg per d for one month with and without an intake of a chelating agent added to the drinking water at a concentration of 10 mmol/l. The chelating agents tested were ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA) and tripolyphosphate (TPP), cysteine and diethyldithiocarbamate (DEDTC). Cysteine and DEDTC gave the highest increase of Bi in tissues but with a wide dispersion of levels. However, even in the rats with the highest levels of Bi, there were no behavioral problems. EDTA induced an increase of Bi in kidney, brain and bone and NTA in kidney but there was no obvious sign of toxicity. We did not succeed in reproducing in rats the Bi toxicity observed in patients some years ago.

Absorption of Bismuth from Several Bismuth Compounds duringin Vivo Perfusion of Rat Small Intestine

“…22 Absorption of Bi from BSN in rats has been shown to be increased by sulflnydryl group-containing compounds, such as 3-mercaptopropionic acid and cysteine, and by complexing agents, such as diethyldithio-carbamate (DEDTC) and ethylenediaminetetraacetic acid (EDTA). 23,24 Citrate was also shown to increase the intestinal absorption of Bi from several Bi compounds in rats. 25 In humans, addition of citrate to a single oral dose of BSN resulted in absorption profiles for Bi in blood and citrate in serum that were parallel, suggesting the formation and absorption of a Bi-citrate Retrospectively, therefore, the choice of a citrate buffer to make the BiC13 perfusates more physiologic was unfortunate because we probably studied the absorption of a Bi-citrate complex and not of BiC13.…”

Renal Pigmentation Due to Chronic Bismuth Administration in a Rhesus Macaque (Macaca mulatta)

“…Normal levels of bismuth in liver and muscle of wild game birds are <0.1ppm, and that in kidneys of rats are <0.2 ppm. 1,5 The renal levels of lead in this macaque were considered within normal limits, disproving lead as the source of the intranuclear inclusions. Although nephrotoxicity due to bismuth has been reported in other species, in this case pigmentation due to bismuth accumulation was not accompanied by clinical or microscopic evidence of toxicity.…”

“…2 The absorption of bismuth from the gastrointestinal tract may be increased under a variety of situations, including patient variation, the formulation of the bismuth compound or salt, time of gastric emptying, alteration of gastric pH, and coadministration of bismuth with products or foodstuffs that contain thiol groups, cysteine, and/or fruit juice. 1,6,7,8 Bismuth is deposited in multiple organs but is retained longest in the kidney. 7 Renal bismuth inclusions have been identified 1 to 30 years after parenteral treatment.…”

Cytotoxicity of Bismuth Compounds to Cultured Cancer Cells

“…It seems that not contrary to the fact that the ratio of free Bi ions in the culture solution is low in the case of organic acid salts such as subgallate. Bi can be detoxified by chelation [10,11], although some amino acids and soil fungi have been shown to enhance its toxicity [8,9]. In this study, we conducted only a very basic examination of cytotoxicity in a human thyroid cancer cell line.…”