Metallothionein methylation

There is concern over the toxicity of a nnmber of metals and metalloids, and their oxyanions. As for antibiotics, the genes for resistance are often plasmid-bome. There are several mechanisms that may operate—redaction, methylation, efflnx, and the synthesis of metal-binding metallothioneins. The following text illustrates aspects of these mechanisms. 

MEOS microsomal ethanol oxidizing system, mercapto- — SH group, metallothionein metal-binding protein, methylation addition of a methyl group. 

Endogenous substances other than metallothionein may be involved in minimizing the effects of heavy metals and excreting them from the body. Hepatic (liver) glutathione, discussed as a phase II conjugating agent in Section 7.4, plays a role in the excretion of several metals in bile. These include the essential metals copper and zinc toxic cadmium, mercury(II), and lead(II) ions and organometallic methyl mercury. 

Ramseier U, Chang JY. Modification of cysteine residues with N-methyl iodoacetamide. Analyt. Biochem. 1994 221 231-233. Bernhard WR. Differential modification of metallothionein with iodoacetamide. Methods Enzymol. 1991 205 426-433. 

Cadmium shares chemical properties with zinc and mercury, but in contrast to mercury, it is incapable of environmental methylation, due to the instability of the monoalkyl derivate. Similarities and differences also exist in the metabolism of Zn, Cd, and Hg. Metallothioneins and other Cd-binding proteins hold or transport Cd, Zn, and Hg within the body. Metallothioneins are metal-binding proteins of relatively low molecular mass with a high content of cysteine residues that have a particular affinity for cadmium, as well as for zinc and copper, and can affect its toxicity. 

Compere, S.J. and R.D. Palmiter. DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells. Cell 25 233—240, 1981. 

Figure 4. Effect of acetaminophen-conjugate substituents on antibody recognition in the acetaminophen-adduct immunoassay. The decrease in inhibition due to particular substituents is shown. These values were calculated by comparing the ability of the following acetaminophen-conjugate analogs to competitively inhibit antibody binding to solid-phase acetaminophen-bound metallothionein. a N-acetyl-L-cysteine compared to 3-(N-acetyl-L-cystein-S-yl)acetaminophen. b acetaminophen compared to 3-(N-acetyl-L-cystein-S-yl)acetaminophen. c 2-(N-acetyl-L-cystein-S-yl)hydroquinone compared to 3-(N-acetyl-L-cystein-S-yD-acetaminophen. d 3-(methylthio)acetanilide compared to 3-(methyl-thiolacetaminophen. e 2-(L-cystein-S-yl)-2-aminophenol compared to 3-(L-cystein-S-ylacetaminophen. f 3-(L-cystein-S-yl)acetaminophen compared to 3-(N-acetyl-L-cystein-S-yl)acetaminophen. g 3-(methyl-thiolacetaminophen compared to 3-(N-acetyl-L-cystein-S-yD-acetaminophen (Reproduced fimm Ref. 14).

P., McCluggage, W.G., Stevenson, M., Phillips, D.H., Hewer, A., Osborne, M.R. Campbell, F.C. (2004a) Modulation of /V-methyl-AFnitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical. 

Once absorbed, metal ions and compounds enter the blood, mostly bound to blood cells and/or plasma proteins, which can be very specific (transferrins, ceruloplasmin). By the bloodstream metals are usually distributed throughout the body. Metallothioneins play an important role in distribution, function, detoxification, and maybe also toxicity of heavy metals [8]. There is a blood-brain barrier which can only be crossed by lipid-soluble molecules. Liver and kidney have a high capacity to bind metals. Bones and other mineralized tissues such as teeth can serve as storage organs for metals such as Ba, Be, Tl, Pb, Sr, La, Y. A number of metals have been shown to cross the placenta and to enter the fetal blood circulation. Biotransformation includes changes in the oxidation state, methylation processes, and cleavage of metal-carbon bonds. Gastrointestinal... 

Gabard B (1976) Improvement of oral chelation treatment of methyl mercury poisoning in rats. Acta Pharmacol Toxicol (Copenh) 39 250-255 Gale GR, Smith AB, Atkins LM, Jones MM (1985) Effects of diethyldithiocarbamate and N-methyl-N-dithiocarboxyglucamine on murine hepatic cadmium metallothionein in vitro. Res Commun Chem Pathol Pharmacol 49 423-434 Gale GR, Smith AB, Jones MM, Singh PK (1992) Evidence of active transport of cadmium complexing dithiocarbamates into renal and hepatic cells in vivo. Pharmacol Toxicol 71 452-456... 

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