Studies related to the mechanism of 3-BHA-induced neoplasia of the rat forestomach.
The major objective of this investigation has been to determine the mechanism by which 3-BHA induces forestomach tumours in rodents. In vitro studies of liver microsomal metabolism of [14C]-3-BHA show binding of metabolites to microsomal protein which could be markedly decreased by addition of L-cysteine. p-Toluenesulphonic acid hydrolysis of the labelled microsomes showed a radioactive peak that co-chromatographed with the major product of the reaction of tert-butylquinone (tert-BuQ) and L-cysteine. In vivo binding of metabolites of [14C]-3-BHA to microsomal protein of the forestomach, glandular stomach and liver was determined. Forestomach microsomal protein contained 14 times as much bound radioactivity as glandular stomach and 12 times as much as liver. HPLC studies showed marked qualitative differences in the distribution of labelled compounds in hydrolysates of microsomes from the three tissues. The forestomach contained peaks not present in the other two tissues. In other studies it was shown that the 3-tert-butyl-5-methoxy-1,2-benzoquinone reacted rapidly with NADPH and NADH. tert-BuQ did so more slowly. Current data suggest that two factors may be of importance for 3-BHA carcinogenesis. The first is thiol depletion resulting from direct binding of quinone metabolites of 3-BHA to tissue thiols. Secondary reactions due to the presence of the quinones could also deplete -SH groups. Such thiol depletion could account for the threshold level existing for 3-BHA carcinogenesis. The second factor is an attack on tissue constituents from reactive metabolites of 3-BHA, as is evident from protein binding, and possibly also from oxygen radicals produced as a result of redox cycling of quinone and hydroquinone metabolites of 3-BHA.
D000818:Animals; D002083:Butylated Hydroxyanisole / Q000378:metabolism / Q000633:toxicity*; D002250:Carbon Radioisotopes; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013274:Stomach Neoplasms / Q000139:chemically induced*
D002250:Carbon Radioisotopes; D002083:Butylated Hydroxyanisole; D009249:NADP