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Identification, Localization and Metal Catalyzed Induction of Specific Metallothionein Isoforms expressed by the Adult Human Lens Brian P. Oppermann Purpose: Metallothioneins (MTs) are a large family of proteins involved in multiple protective pathways, including binding of toxic metals, free radical scavenging, and oxidative stress. We have previously detected increased expression of the MT IIA gene in age-related human cataractous lenses relative to normal, suggesting a role for MTs in the maintenance of lens transparency. The MT family consists of many closely related isoforms grouped into four classes (I-IV). As a first step towards defining the function of MTs in the lens, we sought to establish the range and expression patterns of those MT isoforms expressed by the adult human lens. We also sought to identify those toxic heavy metals that induce MT IIA in cultured human lens epithelial cells (HLEs). Methods: Normal human lenses were microdissected into epithelia and fiber cells. Primers specific for individual MT isoforms were designed. MT transcripts were monitored in whole lenses, epithelia and fibers by RT-PCR and confirmed to be authentic by sequencing. MT protein levels were evaluated by immunoblotting and by immunostaining. Northern analysis, RT-PCR and quantitative mimic RT-PCR were used to characterize MT IIA transcript levels in cultured human lens epithelial cells (SRA 01/04) treated with CuCl2, ZnCl2 and CdCl2 at sub-lethal concentrations known to induce MT in other tissues. Results: Transcripts encoding MT classes I and II but not III or IV were detected in adult human lenses. In addition to MT IIA, five other MT transcripts were identified including IE, IF, IG, IH and IL. MT IIA was detected almost exclusively in the lens epithelium while the class I isoforms were detected at high levels in both lens epithelia and fibers. MT protein was detected almost exclusively in the lens epithelium. CdCl2 and ZnCl2, but surprisingly not CuCl2, induced expression of MT IIA in HLEs. Levels of induction were dependent on metal concentration. The highest levels of MT IIA were detected after 8 hrs of Cd treatment and 3 hours of ZnCl2 treatment. CdCl2 treatment induced MT IIA 1020-fold above basal levels and ZnCl2 induced MT IIA 2-4-fold above basal levels. Conclusions: The present report establishes the spectrum of MTs expressed by the adult human lens, defines their spatial expression patterns in lens epithelia and fibers and demonstrates that MT protein is abundantly present in the lens epithelium. This work also establishes that MT IIA is highly and rapidly induced by CdCl2 and ZnCl2 but surprisingly not by CuCl2 in cultured HLE cells. These data suggest a role for different isoforms of MT in different portions of the lens and also suggests that regulation of MT transcription may play an important role in lens homeostasis and cataract.

Identification, localization and metal-catalyzed induction of specific metallothionein isoforms expressed by the adult human lens