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Attenuation of Azoxymethane-induced Colonic Mucosal Ornithine Decarboxylase and Tyrosine Kinase Activity by Calcium in Rats¹

Veterans Administration Medical Center, Allen Park, Michigan 48101 [F. L. A., S. M. W., A. P. N. M.]; Division of Gastroenterology, Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201 [F. L. A., G. D. L., A. P. N. M.]; and Department of Nutrition and Food Science, Wayne State University, Detroit, Michigan 48202 [A. P. N. M.]

Two in vivo and one in vitro studies were performed to evaluate the chemoprotective role of calcium during the early period of azoxymethane (AOM) induction. In the first set of experiments, groups of male Fischer 344 rats were s.c. injected with either AOM (20 mg/kg) or water (controls) and sacrificed immediately (0 time), and 1, 3, 5, and 7 days postinjection. In the second set of experiments, animals were injected with the same dose of AOM and subsequently pair-fed with rat chow containing either calcium carbonate or diet devoid of added calcium. The amount of calcium consumed was calculated to be 250 mg/kg b.w. In both experiments, colonic mucosa was assayed for ornithine decarboxylase (ODC). In addition, tyrosine kinase (Tyr-k) activity as well as tyrosine specific phosphorylation of membrane proteins were determined. Results revealed that maximal stimulation by AOM of ODC and Tyr-k activity occurred 5 days postinjection. This stimulation was significantly suppressed by calcium. AOM also produced an increase in the rate of tyrosine specific phosphorylation of two distinct colonic mucosal membrane proteins with M_r of 57,000 and 59,000. Again, dietary calcium suppressed the stimulation.

In the third set of experiments, organ culture was utilized. Methylazoxymethanol, the active metabolite of AOM, was used instead of AOM in this part of study. Four hour exposure of mucosal explants to methylazoxymethanol (1 µg/ml) resulted in a significant (20–30%) increase in ODC and Tyr-k activity when compared to controls. Addition of either CaCl₂ (2 µmol/ml) or difluoromethylornithine (2 nmol/ml) the irreversible inhibitor of ODC, significantly suppressed the methylazoxymethanol-induced activity of both ODC and Tyr-k.

We conclude that calcium may have a chemoprotective role and tyrosine kinases may have a regulatory role in the early stages of AOM induction of colon cancer.

¹ Supported by the Veterans Administration Medical Research Service.

² Present address: Henry Ford Hospital, Division of Gastroenterology, 2799 West Grand Boulevard, Detroit, Michigan 48202. To whom requests for reprints should be addressed, c/o A.P.N. Majumdar, Ph.D., D.Sc., at Research Service (151), VA Medical Center, Allen Park, Michigan 48101.

Received 1/20/89. Revised 7/14/89. Accepted 8/ 7/89.

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