Krari N, Mauras Y
Laboratoire de Pharmacologie, Centre Hospialier Universitaire, Angers Cedex, France
Res Commun Mol Pathol Pharmacol. 1995 Sep;89(3):357-64.
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 absorption without leading to encephalopathies. in this paper we have studied in greater detail the toxicity and the pharmacokinetics of Bi, and L-cysteine, given by intraperitoneal route to mice, singly and simultaneously as a Bi-L-cysteine complex. Bismuth and L-cysteine, were nontoxic singly since their LD50 were higher than 15 mmol/kg, but were toxic (LD50 = 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 injection of the Bi-L-cysteine complex suggests that the complex entered into the blood under a non-dissociated form but just afterwards the complex dissociated and the levels of Bi decreased rapidly whereas the levels 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 and L-cysteine given alone. Since the increase of the levels of Bi induced by L-cysteine was not sufficient to explain the increase of the toxicity 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 experiments are needed to verify the validity of this hypothesis.
大约二十年前在法国观察到的铋诱发的脑病从未得到令人信服的解释。在之前的论文中，我们在动物实验中表明，L-半胱氨酸可增强铋的吸收，但不会导致脑病。在本文中，我们更详细地研究了铋和L-半胱氨酸通过腹腔注射给小鼠时单独以及同时以铋-L-半胱氨酸复合物形式给药的毒性和药代动力学。铋和L-半胱氨酸单独使用时无毒，因为它们的半数致死量高于15 mmol/kg，但以复合物形式给药时有毒（半数致死量 = 0.3 mmol/kg）。该复合物的毒性比单独的产品高约50倍。注射铋-L-半胱氨酸复合物后血液中铋和L-半胱氨酸水平随时间的变化表明，该复合物以未解离的形式进入血液，但随后复合物解离，铋的水平迅速下降，而L-半胱氨酸的水平保持较高。当以铋-L-半胱氨酸复合物形式给药时，组织、血液、大脑、肾脏和肝脏中的铋浓度比单独给药时更高。但是，L-半胱氨酸诱导的组织中铋水平的升高不足以解释该复合物与单独给予铋和L-半胱氨酸相比毒性增加50倍的原因。由于L-半胱氨酸诱导的铋水平升高不足以解释复合物毒性的增加，因此需要另一种解释。我们认为这种增加是由铋和L-半胱氨酸对过氧化的刺激引起的，正如铁和L-半胱氨酸的情况一样。需要进行其他实验来验证这一假设的有效性。
