Chemical carcinogens induce cadmium resistance and activate metallothionein genes in cadmium sensitive S49 mouse cells

Treatment of cadmium-sensitive (Cd^s) metallothionein-negative S49 mouse cells with two direct-acting chemical carcinogens (N-ethylnitrosourea or N-acetoxy-2-acetylamino-fluorene) or with u.v. radiation induced a large increase in phenotypically stable cadmium-resistant (Cd^r) variants. In contrast, treatment with any of three agents which alkylate proteins (N-ethylmaleimide, iodoacetate, or phenylmethyl-sulfonyl fluoride) was without effect. Similarly, treatment with 2-acetylaminofluorene (a pre-carcinogen) or with 12-O-tetra-decanoylphorbol-13-acetate (a tumor promoter) did not result in an increase in Cd^r variants. Initial studies indicate that in many variants the metallothionein-I gene, the metallo-thionein-II gene, or both have been activated. Thus the induction of cadmium resistance in Cd^s cells is a potentially useful system to explore the activation of quiescent genes by carcinogens.