Mechanism of Individual Difference in Metallothionein Concentration in the Kidney

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In general Japanese who usually well eat rice containing relatively high concentration of cadmium, renal concentration of cadmium increases with aging because most of the accumulated cadmium remained in the bodies without excreting. It has been known that cadmium induces synthesis of metallothionein, a metal binding protein which reduces toxicity of cadmium, and most of tissue cadmium exists as low toxic complex with metallothionein. We found some Japanese adults with relatively low concentration of metallothionein in the kidney. There is a possibility that the low metallothionein concentration may be induced by genetic disorder. We obtained genomic DNA samples extracted from cortex of kidney of the forensic autopsy samples (103 examples) with written informed consents from the bereaved family of all individuals. By single-stranded conformation polymorphism method and direct sequencing methods, abnormalities of nucleotide sequence of metallothionein gene (exon 1-3) and its promoter region were examined. Single base substitution was found in the promoter region of 19 samples. The substitution observed is A-->G in the 5 bases upstream from the transcription starting point. The mutation (C-->T) in region of exon 3 was also observed in 5 samples. This substitution induces amino acid substitution of Ala-->Vat. All these 5 samples with mutation in exon 3 accompanied with the single base substitution (A-->G) in the promoter described above. However, we could not observed any relationship between these polymorphisms of metallothionein gene and the metallothionein concentration in their kidneys. The low metallothionein concentration observed in Japanese adults may be induced by the reason other than the genetic disorder of metallothionein gene.