Abstract

Metallothionein (MT) proteins are associated with resistance to the toxic effects of heavy metals, chemotherapeutic drugs, and alkylating agents. It has been suggested that MT may mediate both resistance to toxic agents and cellular metal homeostasis. To study the role of MT, we obtained cells expressing a range of MT levels in the absence of heavy metal induction. We cotransfected the eukaryotic G418 resistance vector pSV2neo and mouse MT-1 cDNA in a pBR322 vector into Chinese hamster ovary cells. Of 200 transfected clonal cell populations, five had constitutive MT expression ranging from 31 to 87 ng of MT/mg of protein. All five populations had increased resistance to cadmium but were less resistant to cisplatin than control cells. On the other hand, the level of foreign MT expression correlated well with the degree of cisplatin resistance among the five clones. Resistance to ionizing radiation and growth rate in the absence of drug or radiation treatment were not affected. However, transfected MT gene expression inhibited the ability of Chinese hamster ovary cells to form colonies in the absence of toxic drug treatment (r = -0.95). The perturbation of cisplatin sensitivity after genetic alteration of MT expression indicates a role for MT in drug resistance: however, the fact that transfected MT gene expression decreased rather than increased drug resistance and decreased plating efficiency in the absence of drug implies that the role of MT may not be one of simply "scavenging" toxic molecules. These data suggest a role for MT in homeostatic cellular processes that, when distributed by transfection of active MT genes, have an effect on cellular drug resistance.