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.