Dose-response study on covalent binding to forestomach protein from male F344 rats following oral administration of [14C]3-BHA.
A dose-response study on covalent binding to forestomach protein was performed using male F344 rats following oral administration of [14C]3-tert-butyl-4-hydroxyanisole (3-BHA). The order of tissue distribution of radioactivity 6 h after oral administration of 1% [14C]3-BHA was forestomach greater than glandular stomach greater than liver greater than kidney greater than plasma. The covalent binding levels to forestomach protein were very low until 0.1% 3-BHA, but rapidly increased at concentrations of 1% and 2% 3-BHA. The dose-response relations of 3-BHA levels to the covalent binding to protein coincided well with the incidence of forestomach papilloma reported previously. The binding levels of forestomach and glandular stomach were compared. In case of i.v. administration, both binding levels were almost the same, however, in case of 0.1% p.o. administration, the forestomach level was approximately 8-fold higher than the glandular stomach level. The binding level of forestomach protein by p.o. administration was approximately 54-fold higher than that by i.v. administration. Although the amount of tert-butylhydroquinone (BHQ) was very low compared with the amount of covalent binding, the BHQ levels in forestomach were dependent upon the dose levels of 3-BHA. Our study indicates that the dose-response study on covalent binding to target tissue protein is an efficient method for the quantitative estimation of the active metabolites coming from the chemicals which form the quinone metabolites.
Morimoto
K
K
Division of Xenobiotic Metabolism and Disposition, National Institute of Hygienic Sciences, Tokyo, Japan.
Takahashi
T
T
Okudaira
K
K
Iio
T
T
Saito
Y
Y
Takahashi
A
A
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000378:metabolism*; D006965:Hyperplasia / Q000139:chemically induced; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D010212:Papilloma / Q000139:chemically induced; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000139:chemically induced; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D002273:Carcinogens; D011506:Proteins; D002083:Butylated Hydroxyanisole