Regulation of the isoforms of metallothionein

The objective of this research was to study the regulation of hepatic MT-I and MT-II in rats. Induction of MTs following Cd, Zn, and glucocorticoid treatments was studied in adult rats and the ontogeny of MTs was evaluated in developing rats. The isoforms were quantitated by anion-exchange HPLC and their respective mRNAs were evaluated by Northern blot hybridization with mouse cRNA probes. In untreated adult rat liver, MT-II was more abundant than MT-I. Cd treatment increased MT-I and MT-II to similar concentrations. Low dosages of Zn increased MT-II levels three times higher than MT-I levels, whereas higher dosages increased the isoforms to similar levels. Differences in the degradation of Zn-induced MTs were observed: apparent half-lives for MT-I and MT-II were 12.2 and 21.9 h, respectively. MT-II was the predominant glucocorticoid-inducible isoform. MT-I and MT-II mRNAs increased coordinately after glucocorticoid treatment, but MT-II mRNA was more abundant than MT-I mRNA. In immature rats, MT-I and MT-II were first detected in fetal liver on gestation day 18 and increased to maximum hepatic concentrations during the first week postpartum. Thereafter, MT levels decreased, reaching adult levels by 35 d. In contrast, MT mRNAs reached maximal levels during late gestation that were maintained throughout the first three weeks postpartum. Discoordination between MT mRNA and protein levels is suggestive of translational control of MTs in developing rats. In summary, MT-II is more abundant than MT-I in untreated rats and in rats treated with glucocorticoids or low dosages of zinc. In addition to transcriptional regulations of MTs, translational control of MTs may be important in regulating hepatic MT concentrations, particularly in developing rats, and differences in the degradation of MT-I and MT-II may influence tissue concentrations of the isoforms.