methylnitronitrosoguanidine and sodium-arsenite

The effects of sodium arsenite (As) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on epithelia of human fetal trachea and bronchiolar epithelia of human fetal lung were studied by using organ-cultured explants. In epithelium of human fetal trachea, 34 microM MNNG induced hyperplasia, metaplasia, and dysplasia; 1 microM As induced hyperplasia; and 3-9 microM As induced hyperplasia and cellular atypia. In glandular epithelium of human fetal trachea, 34 microM MNNG induced hyperplasia and metaplasia; 1 microM As did not induce obvious changes; and 3-9 microM As induced hyperplasia and epidermoid metaplasia with nuclear atypia. In bronchiolar epithelium of human fetal lung, the induction of dysplasia was observed for 1 microM As. Arsenic-induced preneoplastic lesions support the conclusion of epidemiological studies that arsenic is carcinogenic to human lung.

Topics: Arsenites; Bronchi; Epithelium; Fetus; Humans; Hyperplasia; Lung; Lung Neoplasms; Methylnitronitrosoguanidine; Organ Culture Techniques; Precancerous Conditions; Sodium Compounds; Trachea; Tracheal Neoplasms

Sodium arsenite (As)-induced DNA damage was measured in human fetal lung fibroblasts (2BS cells) by an alkaline elution technique and a fluorometric DNA assay. Sodium arsenite at 1-5 microM produced DNA-protein crosslinks, while at 10 microM this effect was not observed. Deproteinization of DNA-protein complexes revealed protein-associated DNA-strand breaks. Both DNA-protein crosslinks and DNA-strand breaks were concentration-dependent; 3 microM As was the most efficient dose. Arsenic mediated DNA-protein interactions may play a major role in arsenic carcinogenesis, and the induced protein-associated DNA-strand breaks could provide an explanation for chromosome aberrations and sister-chromatid exchanges induced by arsenic in vivo and in vitro.

Topics: Arsenic; Arsenites; Cells, Cultured; DNA; DNA Damage; Dose-Response Relationship, Drug; Endopeptidase K; Fibroblasts; Humans; Lung; Methylnitronitrosoguanidine; Proteins; Serine Endopeptidases; Sodium Compounds; Sulfhydryl Reagents

The synthesis of a Mr 32,000 protein (p32) is enhanced as early as 2 h after the addition of tumor-promoting phorbol esters to BALB/c 3T3 cells. Among various compounds tested thus far, methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, L-ascorbic acid, sodium deoxycholate, p-tosyl-L-phenylalanine chloromethyl ketone, p-tosyl-L-lysine chloromethyl ketone, 3,3'-diaminobenzidine, and some of the metal salts stimulated the synthesis of p32 to varying extents. p32 might be one of the heat shock proteins because its synthesis was also stimulated by heat shock or sodium arsenite. The synergisms of the effects of different compounds on p32 synthesis suggest that the expression of a p32 gene is regulated through at least three pathways. Possible roles of protein kinases in p32 gene expression are discussed.

Topics: 3,3'-Diaminobenzidine; Animals; Arsenic; Arsenites; Ascorbic Acid; Carcinogens; Deoxycholic Acid; Diglycerides; Diterpenes; Gene Expression Regulation; Hot Temperature; Isoelectric Point; Metals; Methyl Methanesulfonate; Methylnitronitrosoguanidine; Mice; Molecular Weight; Protease Inhibitors; Sodium Compounds; Terpenes