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DNA damage in forestomach epithelium from male F344 rats following oral administration of tert-butylquinone, one of the forestomach metabolites of 3-BHA. 1991

K Morimoto, and K Tsuji, and T Iio, and N Miyata, and A Uchida, and R Osawa, and H Kitsutaka, and A Takahashi
Division of Xenobiotic Metabolism and Disposition, National Institute of Hygienic Sciences, Tokyo, Japan.

DNA damage in the forestomach epithelium of male F344 rats was tested by alkaline elution assay following oral administration of 3-tert-butyl-4-hydroxyanisole (3-BHA) and its free metabolites. Although 1% 3-BHA and 0.001% tert-butylhydroquinone (BHQ) caused no detectable DNA damage, a tert-butylquinone (BQ) treated group showed a significantly higher elution rate than the corn oil and 3-BHA group. Dose-dependent induction of DNA damage in forestomach epithelium by 3-BHA metabolites was compared. BQ showed DNA damaging activity from 0.0001% (1 microgram/ml). On the other hand, BHQ showed the activity at greater than 100 times higher concentration than that of BQ. Six other quinones related to the BQ have been synthesized and examined in vivo for their activity in single strand breaks in forestomach epithelium DNA. The order of the DNA damage was not always correlated with the order of the first reduction potentials of the quinones. 2-Benzylthio-5-tert-butyl-p-benzoquinone (BQSBn-2), 2-phenyl-1,4-benzoquinone and 2,5-di-tert-butyl-p-benzoquinone had higher DNA damaging activity than BQ. The effects of ethylacrylate (EA) pretreatment on the DNA damage by BQ and BQSBn-2 were compared. The DNA damage by BQ was decreased by increasing the EA concentrations. On the other hand, BQSBn-2 had a DNA damaging activity following the EA pretreatment. In order to examine whether 3-BHA is metabolized in forestomach, 3-BHA and BQ levels in the mucosa of forestomach were measured by HPLC with an electrochemical detector. The concentrations of BQ in mucosa correlated with the 3-BHA dose levels from 0.01% to 0.1% 3-BHA. The concentration of BQ in mucosa was approximately 1/4000 of the concentration of 3-BHA in mucosa at the dose level of 1% 3-BHA. The present results indicate that BQ and its thiol conjugates are the active metabolites from 3-BHA in forestomach and may play an important role in inducing carcinogenicity of 3-BHA in F344 rats.

UI MeSH Term Description Entries
D008297 Male Males
D008769 Methylnitronitrosoguanidine A nitrosoguanidine derivative with potent mutagenic and carcinogenic properties. Methylnitrosonitroguanidine,Nitrosomethylnitroguanidine,Nitrosonitromethylguanidine,MNNG,N-Methyl-N'-nitro-N-nitrosoguanidine,N Methyl N' nitro N nitrosoguanidine
D009153 Mutagens Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. Clastogen,Clastogens,Genotoxin,Genotoxins,Mutagen
D011809 Quinones Hydrocarbon rings which contain two ketone moieties in any position. They can be substituted in any position except at the ketone groups.
D011916 Rats, Inbred F344 An inbred strain of rat that is used for general BIOMEDICAL RESEARCH purposes. Fischer Rats,Rats, Inbred CDF,Rats, Inbred Fischer 344,Rats, F344,Rats, Inbred Fisher 344,CDF Rat, Inbred,CDF Rats, Inbred,F344 Rat,F344 Rat, Inbred,F344 Rats,F344 Rats, Inbred,Inbred CDF Rat,Inbred CDF Rats,Inbred F344 Rat,Inbred F344 Rats,Rat, F344,Rat, Inbred CDF,Rat, Inbred F344,Rats, Fischer
D002083 Butylated Hydroxyanisole Mixture of 2- and 3-tert-butyl-4-methoxyphenols that is used as an antioxidant in foods, cosmetics, and pharmaceuticals. Butylhydroxyanisole,(1,1-Dimethylethyl)-4-methoxyphenol,AMIF-72,BHA,Butyl Methoxyphenol,Embanox,Nipantiox 1-F,Tenox BHA,AMIF 72,AMIF72,Hydroxyanisole, Butylated,Methoxyphenol, Butyl,Nipantiox 1 F,Nipantiox 1F
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004848 Epithelium The layers of EPITHELIAL CELLS which cover the inner and outer surfaces of the cutaneous, mucus, and serous tissues and glands of the body. Mesothelium,Epithelial Tissue,Mesothelial Tissue,Epithelial Tissues,Mesothelial Tissues,Tissue, Epithelial,Tissue, Mesothelial,Tissues, Epithelial,Tissues, Mesothelial
D005753 Gastric Mucosa Lining of the STOMACH, consisting of an inner EPITHELIUM, a middle LAMINA PROPRIA, and an outer MUSCULARIS MUCOSAE. The surface cells produce MUCUS that protects the stomach from attack by digestive acid and enzymes. When the epithelium invaginates into the LAMINA PROPRIA at various region of the stomach (CARDIA; GASTRIC FUNDUS; and PYLORUS), different tubular gastric glands are formed. These glands consist of cells that secrete mucus, enzymes, HYDROCHLORIC ACID, or hormones. Cardiac Glands,Gastric Glands,Pyloric Glands,Cardiac Gland,Gastric Gland,Gastric Mucosas,Gland, Cardiac,Gland, Gastric,Gland, Pyloric,Glands, Cardiac,Glands, Gastric,Glands, Pyloric,Mucosa, Gastric,Mucosas, Gastric,Pyloric Gland
D000179 Acrylates Derivatives of acrylic acid (the structural formula CH2

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