DNA binding and stimulation of cell division in the carcinogenicity of styrene 7,8-oxide.
[7-3H]Styrene 7,8-oxide was administered by oral gavage to male CD rats at a dose of 1.3 mg/kg. After 4 h, the forestomach was excised, DNA was isolated, purified to constant specific radioactivity and degraded enzymatically to the 3'-nucleotides. High-performance liquid chromatography fractions with the normal nucleotides contained most of the radiolabel, but a minute level of adduct label was also detected. Using the units of the covalent binding index (micromoles adduct per mole DNA nucleotide)/(millimole chemical administered per kilogram body weight), a DNA binding potency of 1.0 was derived. A comparison of the covalent binding indices and carcinogenic potencies of other genotoxic forestomach carcinogens showed that the tumorigenic activity of styrene oxide is unlikely to be purely genotoxic. Therefore, styrene oxide was compared with 3-t-butylhydroxyanisole (BHA) with respect to stimulation of cell proliferation in the forestomach. Male Fischer 344 rats were treated for four weeks at three dose levels of styrene oxide (0, 137, 275 and 550 mg/kg, three times per week by oral gavage) and BHA (0, 0.5, 1 and 2% in the diet); the highest doses had been reported to result in 84% and 22% carcinomas in the forestomach, respectively. Cell proliferation was assessed by incorporation of bromodeoxyuridine into DNA and immunohistochemical analysis. An increase in the labelling index was found in all treated animals. In the prefundic region of the forestomach, the labelling index increased significantly, from 42% (controls) to 54% with styrene oxide and from 41 to 55% with BHA.(ABSTRACT TRUNCATED AT 250 WORDS)
Lutz
W K
WK
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach, Switzerland.
Cantoreggi
S
S
Velic
I
I
D000284:Administration, Oral; D000818:Animals; D002083:Butylated Hydroxyanisole / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D005753:Gastric Mucosa / Q000378:metabolism; D006965:Hyperplasia; D008297:Male; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000166:cytology / Q000187:drug effects; D013274:Stomach Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D002273:Carcinogens; D004852:Epoxy Compounds; D002083:Butylated Hydroxyanisole; D004247:DNA; C013690:styrene oxide