ENHANCEMENT OF BISMUTH TOXICITY BY L-CYSTEINE

Bismuth-induced encephalopathies observed in France about twenty years ago have never received convincing explanation. In previous papers we have shown in animal experiments that L-cysteine enhanced Bi absorpti on without leading to encephalopathies. In this paper we have studied in greater detail the toxicity and the pharmacokinetics of Bi, and L-c ysteine, given by intraperitoneal route to mice, singly and simultaneo usly as a Bi-L-cysteine complex. Bismuth and L-cysteine, were nontoxic singly since their LD(50) were higher than 15 mmol/kg, but were toxic (LD(50) = 0.3 mmol/kg) when they were given as a complex. The complex was about 50 times more toxic than the separate products. The changes in the levels of Bi and L-cysteine in blood versus time after the inj ection of the Bi-L-cysteine complex suggests that the complex entered into the blood under a non-dissociated form but just afterwards the co mplex dissociated and the levels of Bi decreased rapidly whereas the l evels of L-cysteine remained high. The concentrations of Bi in tissues , blood, brain, kidney and liver were higher when it was given as the Bi-L-cysteine complex than alone. But the increase of the levels of Bi in tissues induced by L-cysteine was not sufficient to explain the 50 fold increase of the toxicity of the complex in comparison with Bi an d L-cysteine given alone. Since the increase of the levels of Bi induc ed by L-cysteine was not sufficient to explain the increase of the tox icity of the complex, another explanation is required. We suggest that this increase results from the stimulation of peroxidation by bismuth and L-cysteine, as already observed for iron and L-cysteine. Other ex periments are needed to verify the validity of this hypothesis.