Activation of H-ras oncogenes in male B6C3F1 mouse liver tumors induced by vinthionine or 2-chloroethyl-methyl sulfide.
Vinthionine (S-vinyl-DL-homocysteine) is hepatocarcinogenic in rats and mice. [Vinyl-14C]vinthionine binds covalently to rat liver DNA, RNA and protein in vivo, but not in vitro. This amino acid is directly mutagenic in Salmonella typhimurium TA100 and TA1535; the mechanism of its metabolic activation in vivo in bacteria and liver is under study. In the present study liver tumors were induced in 12-day-old male B6C3F1 mice by single i.p. injections of vinthionine or the alkylating agent 2-chloroethyl methyl sulfide (CEMS). At 10 months the gross tumors were examined for the presence of activated H-ras oncogenes. DNA was isolated from single tumors per mouse from 37 mice treated with vinthionine and from 31 mice treated with CEMS. These DNAs were screened for codon 61 mutations by restriction fragment length polymorphism of PCR-amplified H-ras gene fragments. Thirty seven of 37 vinthionine-induced hepatomas had H-ras mutations in this codon, which consisted of seven C-->A transversions in the first base, with 29 A-->T transversions and one A-->G transition in the second base. Twenty five of 31 CEMS-induced hepatomas had mutations in the same codon, which consisted of seven C-->A transversions in the first base, with eight A-->T transversions and 10 A-->G transitions in the second base. These mutation spectra are quite different to that noted by others in spontaneous hepatomas in untreated B6C3F1 mice. These data appear to result from the covalent binding of these carcinogens to the liver DNA.
Sohn
Y W
YW
McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, WI 53706, USA.
Lee
G H
GH
Liem
A
A
Miller
J A
JA
D000818:Animals; D001483:Base Sequence; D002273:Carcinogens / Q000633:toxicity*; D005001:Ethionine / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D013440:Sulfides / Q000633:toxicity*
D002273:Carcinogens; D013440:Sulfides; C064671:2-chloroethyl methyl sulfide; C020543:vinthionine; D005001:Ethionine