Role of Clara cells and type II cells in the development of pulmonary tumors in rats and mice following exposure to a tobacco-specific nitrosamine.
The role of the Clara and type II cell in the development of pulmonary tumors in the A/J mouse and Fischer rat was investigated by determining the relationship of DNA methylation and repair in pulmonary cells to oncogene activation and by characterizing the morphology of pulmonary tumors induced by treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Marked differences in the formation of the promutagenic adduct O6-methylguanine (O6MG) were observed in pulmonary cells following treatment of rats with NNK. Concentrations of this adduct in Clara cells greatly exceeded (3- to 30-fold) those detected in type II cells and whole lung with doses of NNK ranging from 0.1 to 50 mg/kg. In addition, very low rates of repair of this adduct were detected in Clara cells, whereas efficient adduct removal occurred in type II cells. The importance of this adduct and the role of cell specificity was suggested by the fact that a strong correlation was observed between the concentration of O6MG in Clara cells and tumor incidence in the Fischer rat with doses of NNK ranging from 0.03-50 mg/kg. In contrast, no differences in adduct concentration between type II and Clara cells from A/J mice were observed under conditions resulting in pulmonary tumor formation. Activation of the K-ras gene was detected in lung tumors from A/J mice. This gene was activated by a mutation in codon 12 involving a GC to AT transition (GGT to GAT) and is consistent with base mispairing produced by the formation of O6MG. Activation of this gene was not associated with lung tumor formation in the Fischer rat. DNA from rat lung tumors did induce tumors in the nude mouse carcinogenicity assay. In addition, rat repetitive sequences were detected in DNA isolated from these nude mouse tumors. In spite of the cell selectivity for DNA methylation in Clara cells from rat and the relationship between O6MG formation and tumorigenicity, early proliferative lesions observed in both mice and rats involved the alveolar areas. Ultrastructural examination of these lesions and adenomas revealed morphologic features characteristic of the type II cell. Thus the lack of agreement between biochemical and morphological findings makes it difficult to hypothesize a cell of origin for the pulmonary neoplasms induced by NNK. However, these studies indicate that the concentration of O6MG in Clara cells is an excellent indicator of the carcinogenic potency of NNK in the rat.(ABSTRACT TRUNCATED AT 400 WORDS)
Belinsky
S A
SA
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
Devereux
T R
TR
White
C M
CM
Foley
J F
JF
Maronpot
R R
RR
Anderson
M W
MW
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000302:isolation & purification; D005784:Gene Amplification / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D008297:Male; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009602:Nitrosamines / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D009857:Oncogenes / Q000235:genetics; D010947:Plants, Toxic; D051381:Rats; D011916:Rats, Inbred F344; D014026:Nicotiana / Q000032:analysis*; D014162:Transfection / Q000235:genetics
D002273:Carcinogens; D004273:DNA, Neoplasm; D009602:Nitrosamines; D006147:Guanine; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase