Induction of colon mucosal β‐glucuronidase production as a mechanism for 1,2‐dimethylhydrazine colon carcinogenesis

Abstract

Although early studies in germ-free rats showed almost complete dependence on dimethylhydrazine (DMH) colon carcinogenesis upon the presence of colon bacteria, no adequate explanation was given for the 20% tumor incidence observed in germ-free animals. Bacterial activation of liver microsomal products releasing active proximate carcinogens has been the accepted reason for the exquisite specificity DMH has for the colon. Recent work, including the present study, show the colon mucosa is capable of metabolizing carcinogens and activating conjugating forms metabolized in the liver independent of the intestinal microflora. Mucosal beta-glucuronidase production was assayed in coded, scraped mucosa samples from the duodenum/jejunum, ileum, right colon, and left colon of normal and DMH-treated rats. Normal mucosal beta-glucuronidase production was highest in the left colon followed by the right colon, duodenum, and ileum, respectively. Enzyme production in the left colon was significantly increased 24 hours after injection of 25 mg/kg body weight DMH. No elevation was seen in other mucosal samples. Metabolism of DMH to oxidated forms conjugated to glucuronic acid is well established. Thus, this study offers a possible role for carcinogen, induction of a metabolic enzyme in its target tissue.

Cellulose and pectin alter intestinal β-glucuronidase (EC 3.2.1.31) in the rat

“…The very low jejunal bacterial population makes it likely that P-glucuronidase has originated from the mucosa of the jejunum. Studies on the enzyme activity of the various segments along the gastrointestinal tract show that P-glucuronidase activity is higher in the left colon than in the right colon and higher in the duodeno-jejunum than in the ileum but with activities in the large intestine significantly greater than in the small intestine (Celik et al 1983).…”

Sericin consumption suppresses development and progression of colon tumorigenesis in 1,2-dimethylhydrazine-treated rats

“…DMH, an alkylating agent, is metabolized and glucuronated by the liver, and excreted via the bile into the gut where microbial β-glucuronidase releases the active carcinogen (Celik et al 1983;Yoo et al 2001). Thus, DMH initiates tumorigenesis within the colon.…”

Possible errors in assay for beta-glycosidase activity

“…For example, the mutagenic metabolites 6-hydroxy-1-acetamidopyrene (10,14,16), quercetin (2,12,18), and kaempferol (1) are released by the hydrolytic actions of BGr, BGl, and BGa on their respective glycosides. In addition, there is evidence for the presence of mucosal BGr in the intestinal tract (2,19,20) and some proof for the existence of mucosal BGa (17). However, it has been suggested that mucosal BGl exists only in the infant rat and disappears by the third week of life (9).…”