EXPOSURE OF HUMAN PROXIMAL TUBULE CELLS TO CD2-2 MESSENGER-RNA(, ZN2+, AND CU2+ INDUCES METALLOTHIONEIN PROTEIN ACCUMULATION BUT NOT METALLOTHIONEIN ISOFORM)

The organization of the human metallothionein (MT) gene family is more complex than the commonly used mouse and rat models. The human MTs ar e encoded by a family of genes consisting of 10 functional and 7 nonfu nctional MT isoforms. One objective of this study was to determine if the accumulation of MT protein in cultures of human proximal tubule (H PT) cells exposed to metals is similar to that expected from the knowl edge base obtained from rodent models. To accomplish this objective, H PT cells were exposed to both lethal and sublethal concentrations of C d2+, Zn2+, Cu2+, Ag2+, Hg2+, and Pb2+ and MT protein levels were deter mined. The results were in general agreement with animal model studies , although there were some exceptions, mainly in areas where the anima l model database was limited. In cleat agreement with animal models, C d2+, Zn2+, and Cu2+ were demonstrated to be potent inducers of MT prot ein accumulation. In contrast to the similarity in MT protein expressi on, we obtained evidence that the human renal MT-2 gene has a unique p attern of regulation compared to both animal models and human-derived cell cultures. In the present study, we determined that MT-2A mRNA was not induced by exposure of HPT cells to Cd2+ or the other metals, a f inding in contrast to studies in both animal models and other human ce ll culture systems in which a high level of MT-2 mRNA induction occurs upon exposure to Cd2+ or Zu(2+). While MT protein expression may be s imilar between humans and animal models, this finding provides initial evidence that regulation of the genes underlying MT protein expressio n may be divergent between species.