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PubMed1982

pH-sensitive mutagenic activity in ozone-treated 1,2-dimethylhydrazine in the Salmonella/microsome assay.

Treatment with ozone inactivates the mutagenicity of many carcinogens in aqueous solution. The colon carcinogen, 1,2-dimethylhydrazine (DMH) has been reported an exception; ozone treatment converts dimethylhydrazine from a non-mutagen into a mutagen. In the Salmonella/microsome assay, the mutagenicity of ozone-treated dimethylhydrazine was dependent on pH. The ozonation product was a strong mutagen in acidic solution but was not mutagenic in basic solution. The mutagenicity of the acidic ozonation product was inactivated by raising the pH of the solution. Unlike untreated dimethylhydrazine, its ozonation product in basic solution was not converted to a mutagen in this ozone-low pH system.

1,2-Dimethylhydrazine↗
PubMed1989

Premalignant alterations in rat colonic N1-acetylspermidine levels induced by 1,2-dimethylhydrazine: effects of a high corn oil dietary regimen.

Recently, our laboratory has demonstrated that elevations in the levels of N1-acetylspermidine could be detected in the colonic mucosa of rats after administration of 1,2-dimethylhydrazine for 15 weeks, i.e., before the development of colon tumors. Since prior studies have indicated that diets high in fat, particularly unsaturated fat, promote the development of dimethylhydrazine-induced tumors, it was of interest to examine the effect of a corn oil dietary regimen (20% by weight) on colonic N1-acetylspermidine levels in this model of colonic adenocarcinoma. Four groups of rats were used in these studies: chow, chow + carcinogen, corn oil and corn oil + carcinogen. The carcinogen groups received weekly s.c. injections of 1,2-dimethylhydrazine (20 mg/kg body wt) for 15 weeks, while the control groups received diluent. 1 week after the last injection, animals from each group were killed, and their proximal and distal colons were resected, examined and compared with respect to polyamine levels, including N1-acetylspermidine, as well as the activities of ornithine decarboxylase, spermidine N1-acetyltransferase, and polyamine oxidase. In view of previous studies which suggested that N1-acetylspermidine levels may be elevated in the urine of patients with various malignancies, it was also of interest to examine and compare the urinary levels of this acetylated polyamine in animals from each group. The results of these experiments demonstrated that: (1) the levels of N1-acetylspermidine in the distal colonic segment were found to be increased approx. 25 and 80% in the chow + carcinogen and corn oil + carcinogen groups, respectively, compared to their control counterparts; (2) the activities of spermidine N1-acetyltransferase in the distal colonic segments of chow + carcinogen and corn oil + carcinogen animals were increased 1.5- and 2-fold, respectively, compared to control values; (3) dimethylhydrazine administration did not affect the levels of this acetylated polyamine or spermidine N1-acetyltransferase activities in the proximal colon, but, in general, did increase the levels of putrescine and spermidine as well as ornithine decarboxylase activities in both colonic segments of animals fed chow or corn oil diets; and (4) elevated urinary levels of N1-acetylspermidine did not appear to be a reliable 'premalignant' marker in this experimental model of colonic adenocarcinoma.

1,2-Dimethylhydrazine↗
PubMed1980

Metabolism of 1,2-dimethylhydrazine by cultured human colon.

The overall metabolism of 1,2-dimethylhydrazine, and organotropic colon carcinogen in rodents, has been studied using human colon explant cultures. The binding level of 1,2-dimethylhydrazine to DNA which in this study includes both reaction of metabolites with DNA and incorporation of radioactive metabolites into DNA, showed a 100-fold variation among the 120 people studied. When different anatomical colonic sites were compared, the highest mean binding levels were found in the ascending and sigmoid colon. No significant difference in the median and mean binding levels were observed in nontumorous colon obtained surgically from patients with colon cancer and colon obtained from immediate autopsy, but decreased mean binding levels were seen in tissues obtained by surgery from patients with non-cancerous colonic disorders. Several exogenous chemicals were found to modify the metabolism. When the colon explants were co-incubated with 1,2-dimethylhydrazine and these chemicals, the binding level of 1,2-dimethylhydrazine to DNA was (a) increased by either indole 3-carbinol or phenobarbital, (b) decreased with disulfiram, butylated hydroxytoluene, or taurodeoxycholic acid, and (c) unaltered by lithocholic acid.

1,2-Dimethylhydrazine↗
PubMed1981

Relationship of colonic mucosal background to neoplastic proliferative activity in dimethylhydrazine-treated mice.

Proliferative activity of background and neoplastic colonic mucosa was examined following five months of weekly injections of 1,2-dimethylhydrazine (20 mg/kg) and one or four months of rest to determine whether previously reported changes may result from an acute or chronic effect of dimethylhydrazine and whether differences exist between stages of neoplasia. To determine whether neoplasia is responsive to a proliferative stimulus, 1,2-dimethylhydrazine dihydrochloride-treated mice were inoculated with Citrobacter freundii. The labeling index and the proliferative zone increased in background mucosa after one month; whereas after four months labeling index, proliferative zone and crypt heights increased, but the mitotic index decreased. There was a positive linear correlation between advancing tumor grade and increasing tumor labeling index and mitotic index. Background labeling index, even when elevated by C. freundii inoculation, had no effect upon tumor labeling index. Mitotic index diminished in background and neoplastic mucosa following prolonged rest and increased in both following C. freundii inoculation. These studies show that 1,2-dimethylhydrazine dihydrochloride causes long-term changes in background mucosa that are apart from a reparative response to cytotoxicity. As tumors progress, labeling index and mitotic index increase, suggesting a multistage process of evolution.

1,2-Dimethylhydrazine↗
PubMed1993

Repair of O6-methylguanine and O4-methylthymidine in F344 rat liver following treatment with 1,2-dimethylhydrazine and O6-benzylguanine.

Concentrations of O6-methylguanine, O4-methylthymidine, and N-7-methylguanine were measured in the livers of Fischer 344 rats following treatment with 1,2-dimethylhydrazine (20 mg/kg, s.c.) alone or in combination with the O6-alkylguanine transferase inhibitor O6-benzylguanine (100 mg/kg, i.p., daily). Animals were sacrificed at 12, 24, 36, or 48 h following 1,2-dimethylhydrazine exposure. Direct measurement of alkyltransferase demonstrated that daily treatment with O6-benzylguanine completely eliminated detectable alkyltransferase activity in the livers of treated rats. Adducts in liver DNA were quantitated by high performance liquid chromatography separation followed by fluorescence detection, UV absorbance, and/or specific radioimmunological assays. In animals exposed to 1,2-dimethylhydrazine alone O6-methylguanine concentrations declined rapidly, whereas animals exposed to both O6-benzylguanine and 1,2-dimethylhydrazine showed less removal of O6-methylguanine, with significant differences between the two populations appearing at 36 and 48 h. O4-Methylthymidine removal also differed significantly between the two groups, with O6-benzylguanine-treated animals exhibiting higher concentrations of adducts at 36 and 48 h. O6-Benzylguanine treatment had no effect on the removal of N-7-methylguanine. These results show that the rate of disappearance of both O6-methylguanine and O4-methylthymidine is slower following alkyltransferase depletion, suggesting that mammalian alkyltransferase is involved in the removal of O4-methylthymidine lesions as well as O6-methylguanine lesions.

1,2-Dimethylhydrazine↗
PubMed1999

The effect of dietary folate on Apc and p53 mutations in the dimethylhydrazine rat model of colorectal cancer.

Dietary inadequacy of folate enhances and folate supplementation suppresses colorectal carcinogenesis in the dimethylhydrazine rat model. Folate is an essential factor for DNA methylation and the de novo biosynthesis of nucleotides, aberrations of which play important roles in mutagenesis. This study investigated whether the mutational hot spots of the Apc and p53 genes for human colorectal cancer are mutated in dimethylhydrazine-induced colorectal neoplasms and whether dietary folate can modulate mutations in these regions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg folate/kg diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for 15 weeks. Mutations were determined by direct sequencing in 11 low and seven high grade dysplasias and 13 invasive adenocarcinomas. A total of six Apc mutations were found in four dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one high grade dysplasia and two in one adenocarcinoma. All mutations were single base substitutions, four of which were A:T-->G:C transitions. Five of the six mutations were located upstream from the region corresponding to the human APC mutation cluster region. Dietary folate had no effect on the frequency and type of Apc mutations. No mutations were detected in exons 5-9 of the p53 gene in neoplastic lesions. These data suggest that in the dimethylhydrazine rat model of colorectal cancer, the Apc gene is mutated in early stages, albeit to a lesser degree than observed in human colorectal cancer, whereas the mutational hot spot of the p53 gene for human colorectal cancer is not commonly mutated. Although the low frequency of Apc mutations and the small number of neoplasms studied in this study might have precluded our ability to observe modulatory effects of folate, dietary folate appears to have no significant effect on Apc and p53 mutations.

Animals↗
PubMed1983

Modification of the carcinogenic process in colorectal cancer by endogenous and exogenous factors: effect of colestipol hydrochloride on tumors induced by dimethylhydrazine.

The effect of the bile acid sequestrant, colestipol hydrochloride, on the incidence of dimethylhydrazine-induced tumors of the large intestine was determined in male Swiss mice. The subcutaneous administration of dimethylhydrazine (15 mg/kg) produced tumors in approximately 89% of the animals with an average of 1.70 tumors per tumor-bearing animal. When carcinogen-treated animals received dietary colestipol (0.52%, w/w) from 4 weeks prior to the first injection of dimethylhydrazine until the time of death, there was an increase in the number of tumors per tumor-bearing animal to 2.23. In an attempt to understand the nature of this enhancement, animals were administered dietary colestipol at different times in relation to the administration of the carcinogen. The number of tumors per tumor-bearing animal for the different protocols was: post-initiation colestipol exposure, 1.70; colestipol exposure concomitant with dimethylhydrazine, 1.41; pre-initiation colestipol exposure, 2.23. Thus, colestipol appeared to function both as an anticarcinogen and as a promoter (pre-initiation). Since colestipol has the capacity to bind a number of chemical agents, the different biological effects probably reflect the multifactorial nature of colorectal cancer with the end result dependent on the balance between opposing factors. The selective administration of colestipol in relation to carcinogen administration may prove useful in elucidating the various factors involved in the etiology of this disease.

Animals↗
PubMed1976

Early effects of a single intrarectal dose of 1,2-dimethylhydrazine in mice.

The early morphological and biochemical effects of intrarectally administered 1,2-dimethylhydrazine dihydrochloride on mouse colon were studied. Using [3H]thymidine autoradiography, it was found that 1,2-dimethylhydrazine dihydrochloride, 250 mg/kg decreased the number of prelabeled DNA-synthesizing cells in the distal colon as early as 30 min after instillation. During the interval from 24 hr to 2 weeks, however, the opposite effect was seen; incorporation of [3H]thymidine increased 3- to 5-fold over controls. At lower doses (0.25 to 25 mg/kg), a similar trend was observed. Histological examination showed no dramatic changes in cell structure or in tissue architecture. No changes were seen in labeling indices in the proximal colon. In the liver, cellular alterations were seen at concentrations of 25 to 250 mg/kg, particularly in the centrolobular region. These changes were evident at 2 hr and disappeared by 4 hr. The kidney was unaffected by 1,2-dimethylhydrazine dihydrochloride at any concentration. Our results suggest that enzymes capable of activating 1,2-dimethylhydrazine dihydrochloride are located within the mucosal cells of the distal colon.

Animals↗
PubMed1983

Evidence for an adenoma-carcinoma sequence in dimethylhydrazine-induced neoplasms of rat intestinal epithelium.

Carcinogen-induced primary intestinal adenocarcinomas serve as a useful animal model for human colonic adenocarcinomas. Although striking similarities between this model and the human disease state exist, there are also troublesome discrepancies-a major one being the reported lack of an adenoma-carcinoma sequence in the experimental model. However, the original morphologic descriptions of these experimental neoplasms predated the development of presently accepted morphologic criteria that have been used to describe the adenoma-carcinoma sequence in humans. Therefore, the authors reevaluated the structural evolution of dimethylhydrazine-induced rat intestinal neoplasms, using the same criteria that were recently applied to evaluate human colonic adenocarcinomas. Such an approach shows that many dimethylhydrazine-induced intestinal adenocarcinomas have peripheral foci of adenomatous epithelium associated with them. In addition, the frequency of this association correlates inversely (P less than .001) with the depth of invasion. These findings are comparable to those which, in humans, have been used as evidence supporting the adenoma-carcinoma sequence. Thus, when assessed with equivalent criteria, dimethylhydrazine-induced intestinal adenocarcinomas appear to be similar, not dissimilar, to human colonic adenocarcinomas in their structural evolution. These data suggest that, at least in part, dimethylhydrazine-induced intestinal adenocarcinomas arise in foci of preexisting adenomatous epithelium.

Adenocarcinoma↗
PubMed1982

Effects of delays in the cell cycle on the induction of preneoplastic and neoplastic lesions in rat liver by 1,2-dimethylhydrazine.

This study was designed to explore further the relationship between cell proliferation and the induction of early putative preneoplastic lesions by carcinogens. Rats were given a non-necrogenic dose of 1,2-dimethylhydrazine 24 hr before being subjected to partial hepatectomy. Beginning 4 hr later, hydrocortisone was injected 10 times at 4-hr intervals to delay progression through the cell cycle, including inhibition of DNA synthesis by at least 85% for about 40 hr. At the appropriate time thereafter, the putative preneoplastic hepatocytes were selectively stimulated to grow in vivo into gamma-glutamyltransferase-positive focal lesions. Animals given hydrocortisone showed a large decrease (71%) in the number of gamma-glutamyltransferase-positive foci. In contrast, when hydrocortisone was given at 6 days after partial hepatectomy, no inhibition in the induction of hepatic lesions was observed. In the next experiments, rats were treated with 1,2-dimethylhydrazine and were subjected to partial hepatectomy at 12, 24, or 48 hr or 1 week thereafter. A significant number of gamma-glutamyltransferase-positive foci was found when partial hepatectomy was performed at 12 or 24 hr but far fewer were found when the operative partial hepatectomy was delayed to 48 hr or 1 week later. Similarly, in long-term experiments, six of 14 animals developed primary hepatocellular carcinoma 13 months after the time of injection of 1,2-dimethylhydrazine when partial hepatectomy was performed at 12 hr, while none of the animals developed liver cancer when the operation was performed at 48 hr. These results imply that the majority of biochemical lesions induced by 1,2-dimethylhydrazine that are relevant to the induction of liver preneoplasia and neoplasia are short-lived and that their persistence is associated with some cellular activity closely related to the cell cycle.

Animals↗
PubMed1981

Effect of inhibitors of tumorigenesis on the formation of O6-methylguanine in the colon of 1,2-dimethylhydrazine-treated rats.

The level of O6-methylguanine (O6MeGua) in the colonic DNA of rats treated with 1,2-dimethylhydrazine was determined. The effect of various tumorigenesis inhibitors on the formation of this modified base was also studied. Rats were given a single s.c. injection of 1,2-[14C]dimethylhydrazine. Six hr later, they were killed, and colonic DNA was extracted and analyzed by high-pressure liquid chromatography. The inhibitors tested were disulfiram (DSF), pyrazole, sodium selenite, butylated hydroxyanisole, butylated hydroxytoluene, potassium ascorbate, and 13-cis-retinoic acid. The level of O6MeGua in control rats was 29.9 [(O6MeGua X 10(6)/guanine)]. When rats were fed 0.25% (w/w) DSF, this value was reduced to 10.2, and at 0.5% DSF there was no detectable O6MeGua formed. Injection of pyrazole (40 mg/kg i.p.) 2 hr prior to 1,2-dimethylhydrazine treatment reduced the O6MeGua level to 2.4. All the other tumorigenesis inhibitors had no effect on either O6MeGua levels or the cpm/mg DNA in treated rats. With O6MeGua as a measure of the extent of initiation, these results confirm that DSF and pyrazole inhibit the initiation phase of carcinogenesis. This is to be expected as both have been shown to block the metabolism of azoxymethane, which is a crucial metabolite in the activation of 1,2-dimethylhydrazine. The other substances, all known tumorigenesis inhibitors, may act on the promotional phase of carcinogenesis and are worthy of further study for the role in cancer prevention.

Animals↗
PubMed1988

1,2-Dimethylhydrazine-induced alterations in Na+-H+ exchange in rat colonic brush-border membrane vesicles.

1,2-Dimethylhydrazine, in weekly subcutaneous (s.c.) doses of 20 mg/kg body weight, produces colonic tumors in virtually 100% of rodents, with a latency period of approximately 6 months. To determine whether alterations in Na+-H+ exchange existed before the development of dimethylhydrazine-induced colon cancer, rats were given s.c. injections of this agent (20 mg/kg body wt. per per week) or diluent for 5 weeks. Animals were then killed, rat colonic brush-border membrane vesicles prepared and amiloride-sensitive sodium-stimulated proton efflux was measured and compared in control and treated-preparations. The results of these studies demonstrated that dimethylhydrazine treatment: (1) significantly increased the Vmax of this exchange without altering the Km for sodium of this exchange process, utilizing the fluorescent pH-sensitive dye, acridine orange; 22Na flux experiments also demonstrated an increase in amiloride-sensitive proton-stimulated sodium influx across treated-membrane vesicles; (2) did not appear to significantly influence Na+ permeability or proton conductance in treated-preparations compared to their control counterparts; and (3) did not significantly affect the kinetic parameters of amiloride-sensitive sodium-stimulated proton efflux in renal cortex brush-border membrane vesicles using acridine orange. This data, therefore, suggests that alterations in Na+-H+ exchange in rat colonic brush-border membranes may be involved in the malignant transformation process induced by this procarcinogen in the large intestine.

1,2-Dimethylhydrazine↗
PubMed1988

1,2-Dimethylhydrazine-induced premalignant alterations in the S-adenosylmethionine/S-adenosylhomocysteine ratio and membrane lipid lateral diffusion of the rat distal colon.

Prior studies by our laboratory, utilizing the 1,2-dimethylhydrazine experimental model of colonic cancer, had shown that administration of this procarcinogen for 5 weeks was found to increase phospholipid methyltransferase activity and the fluidity of rat distal colonic brush-border membranes. The present studies were conducted to further explore these 'premalignant' colonic phenomena. Male albino rats of the Sherman strain were subcutaneously injected with dimethylhydrazine (20 mg/kg body weight per week) or diluent for 5 weeks. Animals from each group were killed, distal colonic tissue harvested and the levels of S-adenosylmethionine, S-adenosylhomocysteine and decarboxylated S-adenosylmethionine measured by high performance liquid chromatography. The activity of methionine adenosyltransferase was also examined in these tissues. Additionally, brush-border membranes were isolated from the distal colonocytes of control and treated-animals and examined and compared with respect to their phospholipid methylation activities as well as their lipid fluidity as assessed by the rotational mobilities of the probes 1,6-diphenyl-1,3,5-hexatriene and DL-12-(9-anthroyl)stearic acid and translational mobility of the fluorophore pyrenedecanoic acid. The results of these studies demonstrated: (1) phospholipid methyltransferase activity in rat colonic plasma membranes was increased concomitantly with increases in the cellular levels of S-adenosylmethionine and the S-adenosylmethionine/S-adenosylhomocysteine ratio in the distal colonic segment of treated-animals; and (2) the lateral diffusion of rat distal colonic brush-border membrane lipids, as assessed by the ratio of excimer/monomer fluorescence intensities of the fluorophore pyrenedecanoate, was also increased after dimethylhydrazine administration to these animals for 5 weeks.

1,2-Dimethylhydrazine↗
PubMed1990

1,2-Dimethylhydrazine-induced alterations in lipid peroxidation in preneoplastic and neoplastic colonic tissues.

To determine whether alterations in lipid peroxidation existed in the preneoplastic and neoplastic colonic tissues of animals treated with the procarcinogen 1,2-dimethylhydrazine, rats were injected subcutaneously with this agent (20 mg/kg body weight per week) or diluent for 5, 10, 15 and 26 weeks. At each of these time periods, animals from both groups were sacrificed, their distal colonic mucosa and/or tumors harvested, and examined and compared with respect to malondialdehyde and lipofuscin-like pigments levels. Additionally, at 26 weeks, the fatty acid composition of microsomes prepared from control, 'uninvolved' and tumor colonic tissues were analyzed and compared. The results of these experiments demonstrated that: (1) the levels of these products of lipid peroxidation were similar in the distal colons of all animals at 5 and 10 weeks; (2) at 15 weeks, however, lipid peroxidation was decreased in the distal colons of animals treated with dimethylhydrazine; (3) at 26 weeks, the levels of these products of lipid peroxidation remained lower in dimethylhydrazine-treated distal 'uninvolved' colonic mucosa and was, moreover, markedly decreased in colonic tumors; and (4) at this latter time period, differences in the fatty acid composition between tumor, 'uninvolved' and control tissues were found. These differences, however, did not appear to underlie the changes noted in the lipid peroxidation products seen in these tissues. Taken together, these findings suggest that alterations in lipid peroxidation may be involved in the colonic malignant transformation process in this experimental model.

1,2-Dimethylhydrazine↗
PubMed1981

Utilization of blood analyses to evaluate metabolic changes in control and 1,2-dimethylhydrazine-treated adult male fischer rats.

The synthetic compound 1,2-dimethylhydrazine is employed in carcinogenesis studies because of its reliable and specific ability to produce colon tumors in rodents. Male Fischer rats were treated at 7 weeks of age with a single oral dose of 1,2-dimethylhydrazine (35 mg/kg) and examined at autopsy 1.5 years later when the incidence of colon tumors is approximately 80%. Blood from control and 1,2-dimethylhydrazine-treated animals was taken at autopsy for routine hematoplazia analysis and for biochemical analysis with the Sequential Multiple Analyzer Computer multitest system. The results indicate that the induction of tumors with a single oral dose of this carcinogen is associated with statistically significant changes in the serum levels of some clinically useful metabolic parameters. Clinically significant changes in the serum chemistry were increases in the creatine phosphokinase (CPK) and albumin/globulin values without an increase in the total serum protein. The multitest system has not been previously employed to evaluate the blood chemistry profiles of tumor-bearing animals and, thus, this study provides an illustration of the potential for this technique to evaluate metabolic changes associated with exposure to carcinogens.

1,2-Dimethylhydrazine↗
PubMed1983

Development of rat liver and colon substrate cycle enzymes in offspring with and without prenatal exposure to a carcinogenic dose of 1,2-dimethylhydrazine.

Pregnant F-344 rats were exposed by intubation to a single dose (35 mg/kg) of 1,2-dimethylhydrazine dihydrochloride or to an acetate buffer on day 14 of gestation. A detailed examination of the effects of this dose of 1,2-dimethylhydrazine on brush border enzymes in the offspring was performed. Changes in the liver and colon levels of the alpha-glycerophosphate and malate/aspartate substrate cycle enzymes were measured during the development; at days 17 and 20 of gestation and at 2, 6, 13, 20, 27, 55, 110 days and 1 year after birth. It is concluded that metabolic energy enzymes, glutamate oxaloacetate transaminase and malate dehydrogenase, are more sensitive to 1,2-dimethylhydrazine treatment than are the brush border hydrolases or NAD- and Fp-linked alpha-glycerophosphate dehydrogenases.

1,2-Dimethylhydrazine↗
PubMed1991

Changes in the activities of jejunal glucosidases in experimental intestinal tumorigenesis induced by 1,2 dimethylhydrazine in rats fed different diets.

The purpose of the present study was to establish the effect of the carcinogen 1,2 dimethylhydrazine on the activities of the jejunal glucosidases and to assess the possible modifying effect of different diets. Two control groups of Wistar albino rats were used - fed standard pellet diet and fed the same diet + 1,2 dimethylhydrazine treatment. Six experimental groups treated with 1,2 dimethylhydrazine were provided. One of them was fed standard diet, containing 30% of wheaten bran and the other 5 groups received high-lipid diets, containing 30% of different fats. The rats were injected subcutaneously once a week for 12 weeks with 20 mg 1,2 dimethylhydrazine/kg b.m. and left for 12 weeks in order to develop a tumor growth. The activities of 5 glucosidases (lactase, maltase, sucrase, palatinase and cellobiase) were determined in homogenates from jejunal mucosa taken near by the tumors and in homogenates from the tumors themselves. An expressed decrease of the jejunal glucosidase activities near the tumors and in the tumors was established. The animals fed 30% wheaten bran diet did not develop tumorigenesis and showed comparatively slight decrease of the enzyme activities. In general, the high-fat regimens did not exert such a preventive effect.

1,2-Dimethylhydrazine↗
PubMed1994

Dietary sphingomyelin inhibits 1,2-dimethylhydrazine-induced colon cancer in CF1 mice.

Sphingolipids are in all eukaryotic cells and modulate cell growth, differentiation, and transformation; however, little is known about the physiological effects of their consumption. Mice were fed diets supplemented with milk sphingomyelin to determine effects on colon carcinogenesis. Cancer was initiated in CF1 mice by 1,2-dimethylhydrazine. Mice were then fed AIN76A diets supplemented with 0.025 to 0.1 g sphingomyelin/100 g for 28 wk until the supply of sphingomyelin was depleted and then fed unsupplemented diet for 24 wk. Sphingomyelin did not affect weight gain. Mice fed sphingomyelin had a 20% incidence of colon tumors compared with 47% in controls (P = 0.08 for all sphingomyelin-fed mice vs. controls). Tumors were adenomas or adenocarcinomas and located in the distal third of the colon. In shorter-term studies, colonic epithelial cell proliferation was significantly greater than controls in mice fed 0.025 g sphingomyelin/100 g diet, but not in those fed higher amounts of sphingomyelin. The number of aberrant crypts was significantly lower in 1,2-dimethylhydrazine-treated mice fed 0.05 g sphingomyelin/100 g diet than in controls. These results demonstrate that consumption of sphingomyelin affects the behavior of colonic cells. Because sphingolipids are present in food, the reduction in 1,2-dimethylhydrazine-induced premalignant lesions and the incidence of colon tumors in CF1 mice implies that these compounds may be another important class of nutritional modulators of carcinogenesis.

1,2-Dimethylhydrazine↗