- Full (HTML) - Related EHP Articles - PubMed:Related Articles - PubMed:Citation - Cited in PMC - Purchase This Issue

Scott H. Garrett, Seema Somji, John H. Todd, and Donald A. Sens

Robert C. Byrd Health Sciences Center, Department of Pathology, West Virginia University, Morgantown, WV 26506

Abstract

The organization of the human metallothionein (MT) gene family is more complex than the commonly used mouse and rat models. The human MTs are encoded by a family of genes consisting of 10 functional and 7 nonfunctional MT isoforms. One objective of this study was to determine if the accumulation of MT protein in cultures of human proximal tubule (HPT) cells exposed to metals is similar to that expected from the knowledge base obtained from rodent models. To accomplish this objective, HPT cells were exposed to both lethal and sublethal concentrations of Cd²⁺, Zn²⁺, Cu²⁺, Ag²⁺, Hg²⁺, and Pb²⁺ and MT protein levels were determined. The results were in general agreement with animal model studies, although there were some exceptions, mainly in areas where the animal model database was limited. In clear agreement with animal models, Cd²⁺, Zn²⁺, and Cu²⁺ were demonstrated to be potent inducers of MT protein accumulation. In contrast to the similarity in MT protein expression, we obtained evidence that the human renal MT-2 gene has a unique pattern 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 finding in contrast to studies in both animal models and other human cell culture systems in which a high level of MT-2 mRNA induction occurs upon exposure to Cd²⁺ or Zn²⁺. While MT protein expression may be similar between humans and animal models, this finding provides initial evidence that regulation of the genes underlying MT protein expression may be divergent between species. Key words: cadmium, copper, gene regulation, lead, mercury, metallothionein, mRNA expression, nephrotoxicity, proximal tubule, silver, zinc. Environ Health Perspect 106:587-595 (1998) . [Online 17 August 1998]

http://ehpnet1.niehs.nih.gov/docs/1998/106p587-595garrett/ abstract.html

Address correspondence to D.A. Sens, Department of Pathology, West Virginia University, P.O. Box 9203, Morgantown, WV 26506-9203 USA.

This publication was made possible by grant number ESO7687 from the National Institute of Environmental Health Sciences.

Received 14 January 1998 ; accepted 11 May 1998.