Ki-ras mutations in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-initiated and butylated hydroxytoluene-promoted lung tumors in A/J mice.
The promotional effects of butylated hydroxytoluene (BHT) on lung tumorigenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was evaluated in a two-stage model of lung tumorigenesis in the A/J mouse. Mice were treated in two separate experiments with 1.54 mmol/kg (9.1 mg/mouse) NNK, which induced an average of 8.4 and 9.1 tumors/mouse in the experiments. Animals fed a diet that contained 1 g/kg BHT after administration of the carcinogen in these two experiments demonstrated an increase of the tumor multiplicity by 63% and 43%. Multiplicity of forestomach tumors was not effected by BHT in the diet. No differences in lung tumor morphology were seen as a result of the promoting effect of BHT. Mutations in the Ki-ras oncogene from lung tumors induced by NNK (19 tumors) or by NNK plus a diet containing BHT (34 tumors) were characterized by polymerase chain reaction, single-strand conformational polymorphism, and direct sequencing. All 19 NNK-induced tumors not promoted with BHT contained activated Ki-ras genes with GC-->AT transitions at the second base of codon 12. Only 11 of 34 NNK-induced and BHT-promoted tumors (32%) had this characteristic Ki-ras alteration. These data suggest that the NNK-initiated mouse lung tumorigenesis pathway, which involves the specific mutation of the Ki-ras oncogene, is altered to a predominantly non-ras mechanism when these tumors are promoted by BHT in the diet.
Matzinger
S A
SA
Department of Pathology, Medical College of Ohio, Toledo.
Gunning
W T
WT
You
M
M
Castonguay
A
A
D000236:Adenoma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002084:Butylated Hydroxytoluene; D002273:Carcinogens; D005260:Female; D011905:Genes, ras; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008805:Mice, Inbred A; D008969:Molecular Sequence Data; D009154:Mutation; D009602:Nitrosamines; D010212:Papilloma / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D016133:Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000473:pathology
D002273:Carcinogens; D009602:Nitrosamines; D002084:Butylated Hydroxytoluene; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone