Sequential morphological and biological changes in the glandular stomach induced by oral administration of catechol to male F344 rats.
Histogenesis and mechanisms of catechol-induced rat glandular stomach carcinogenesis were investigated in male F344 rats. Groups of 5 or 6 rats were treated with dietary catechol at doses of 1, 0.5, 0.1, and 0.01% for 12 hr or for 1, 2, 3, or 7 days or at a dose of 0.8% for 1, 2, 4, 12, and 24 wk; rats were then euthanatized. The initial morphological changes were edema of the gastric wall, inflammatory-cell infiltration, erosion in the pyloric region close to the duodenum, and considerable increase in apoptosis at 12 hr; later, changes included augmented DNA synthesis and cell proliferation, as evaluated by bromodeoxyuridine labeling index and thickness of mucosa, respectively, on day 1. Downward hyperplasia due to excess regeneration appeared at edges of ulceration at week 2. This lesion disappeared, and then submucosal hyperplasia appeared in the course of adenoma development. Only slight expression of c-myc or c-fos was apparent after 30-min oral administration or 1-, 3-, and 6-hr oral administration of catechol. No increase in lipid peroxide levels was evident in gastric epithelium fed catechol for 1 wk. The amount of catechol distributed in the glandular stomach and forestomach epithelium, which is not a target for carcinogenesis, did not differ 1, 3, 6, and 24 hr after a single intragastric dose of 75 mg/kg body weight. Amounts of catechol bound to tissue protein were also not specifically high in the glandular stomach. These results indicate that regenerative cell proliferation due to toxicity plays an important role in catechol-induced glandular stomach carcinogenesis. Protein binding and free radicals may not be largely responsible for the toxicity.
Hirose
M
M
First Department of Pathology, Nagoya City University, Medical School, Nagoya, Japan. m-hirose@nihs.go.jp
Hakoi
K
K
Takahashi
S
S
Hoshiya
T
T
Akagi
K
K
Lin
C
C
Saito
K
K
Kaneko
H
H
Shirai
T
T
D000284:Administration, Oral; D000818:Animals; D002396:Catechols / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000187:drug effects* / Q000473:pathology; D013997:Time Factors
D002396:Catechols; C034221:catechol