Metallothionein renal synthesis

Bismuth and zinc are known to be potent inducers of renal metallothionein (MT) synthesis, and pretreatment with bismuth significantly reduces the renal and lethal toxicity of cisplatin without affecting its anticancer activity in human patients [146], The protection probably involves Bi induction of metallothionein synthesis. UV and NMR studies have shown that Bi° binds very strongly... 

In vivo mercury exposure does induce the synthesis of metallo-thionein in the kidney. The absolute amount of thionein bound mercury, however, usually is small for example, less than 2% of the total renal content at 24 hr after the injection of 0.5 mg Hg2+/kg body weight into the male rat (Webb and Magos, 1976). In contrast, at low-level cadmium exposure, most of the metal accumulated in the kidney is bound to metallothionein. The synthesis of this metalloprotein under these conditions parallels the renal uptake of cadmium until, at least, old age (Cain et al., unpublished). The critical renal concentration at which kidney dysfunction occurs at chronic exposure is high - about 200 yg Cd /g wet weight (Friberg et al., 1974), since only about 20% of this cadmium will be in the toxic non-thionein bound form. 

Cadmium (soft, Cd2+) Renal toxicity Blocks sulfhydryl groups in enzymes and competes with zinc. Stimulates metallothionein synthesis and interferes with Cu(II) and Zn(II) metabolism. 

Nordberg GF, Jin T, Nordberg M. Subcellular targets of cadmium nephrotoxicity cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. Environ Elealth Perspect 1994 102 (suppi 3) 191-194. 

A striking feature of the cellular effects of bismuth compounds in animals (and one shared only by lead) is the production of intranuclear inclusion bodies of up to 5 ixm in diameter (87), for example, in the tubular epithelial cells of the kidney. Electron probe microanalysis shows that these contain both Bi and S, and so could be a complex with a Cys-rich protein such as metallothionein. Bismuth is known to be a potent inducer of renal metallothionein synthesis, and pretreatment of animals with bismuth salts can prevent some of the toxic side effects induced by cisplatin (88). The role of metallothionein in the pharmacology of bismuth remains to be established, but the strong involvement of zinc, also an inducer of metallothionein synthesis, in the metabolism of skin cells, for example, may be related. Like several other elements of Group V, the development of the biological chemistiy of Bi is hampered by the lack of good physical properties, in particular of a well-behaved NMR isotope. 

In contrast to inorganic mercury, alkyl mercuries do not induce metallothionein synthesis in renal or liver cells. 

Nordberg GF, Jin T, Nordberg M. Subcellular targets of cadmium nephrotoxicity cadmium binding to renal membrane proteins in animals with or without protective metallothionein synthesis. Environ Flealth Perspect 1994 102(suppl 3) 191-194. Fowler BA, Akkerman M. The role of Ca + + In cadmium-induced renal tubular cell Injury.. In Cadmium in the human environment toxicity and carcinogenicity. Nordberg G, Herber R, Alessio L (editors). International Agency for Research on Cancer (lARC) Scientific Publications vol 118, Lyon 1992 p. 271-277. 

Naganuma a, Satoh M and Imura N (1987) Prevention of lethal and renal toxicity of cis-diamine-dichloroplatinum(II) by induction of metallothionein synthesis without compromising its antitumour activity in mice. Cancer Res 47 983-987. 

In liver cells, methylmercury forms soluble complexes with cysteine and glutathione, which are secreted in bile and reabsorbed from the G1 tract. In general, however, organomercurials undergo cleavage of the carbon-mercury bond releasing ionic inorganic mercury. Mercuric mercury induces synthesis of metallothioneins, mainly in kidney cells. Mercury within renal cells becomes localized in lysosomes. 

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