Supplemental dietary calcium fails to alter the acute effects of 1,2-dimethylhydrazine on O6-methylguanine, O6-alkylguanine-DNA alkyltransferase and cellular proliferation in the rat colon.
Prior studies from our laboratory have demonstrated that K-ras G to A mutations were detectable in a high percentage of carcinomas which developed in the colons of animals treated with the known colonic procarcinogen, 1,2-dimethyl-hydrazine (DMH). Moreover, in this model, the incidence of these mutations was decreased by a supplemental dietary calcium regimen which concomitantly decreased the frequency of rats with multiple tumors as well as tumor size. In an attempt to clarify the possible mechanism(s) involved in this antimutagenic effect of supplemental calcium, two groups of Sprague-Dawley rats were fed semisynthetic diets containing either 0.87 or 1.80% calcium by weight for 3 weeks, s.c. injected with 100 mg/kg of DMH and killed prior to and at various time periods (16-144 h) after injection. The colons of animals were analyzed and compared with respect to O6-methylguanine content in DNA, O6-alkylguanine-DNA alkyltransferase levels as well as cellular proliferation, as assessed by immunohistochemical staining of colonic crypts by bromodeoxyuridine. In certain experiments, these parameters were also analyzed in the proximal and distal colon before and at various times after administration of DMH. The results of these experiments demonstrated that supplemental dietary calcium was not found to influence significantly O6-methylguanine levels, alkyltransferase levels or cellular proliferation in the entire colon or in either colonic segment before or after the acute administration of DMH. DMH did, however, differentially alter all three of these biochemical parameters in the colonic segments (distal > proximal), possibly due to a greater degree of metabolic activation in the distal colon.
Department of Medicine, University of Chicago, Pritzker School of Medicine, IL 60637.
R F
RF
Jacoby
M J
MJ
Bolt
M E
ME
Dolan
G
G
Otto
P
P
Dudeja
M D
MD
Sitrin
T A
TA
Brasitus
D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D001711:Biotransformation; D002118:Calcium / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000378:metabolism; D004032:Diet; D004127:Dimethylhydrazines / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D016587:Antimutagenic Agents; D004127:Dimethylhydrazines; D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002118:Calcium