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PubMed1982

Dimethylhydrazine-induced colonic neoplasia: dissociation from endogenous gastrin levels.

The potential tropic effect of gastrin in promoting colonic carcinogenesis was tested in rats (n = 133) with 6- to 16-fold variations in endogenous gastrin resulting from antrectomy or fundectomy, followed by 12 injections of 1,2-dimethylhydrazine (10 mg/kg). The incidence and grade of differentiation of resulting tumors, as well as the thickness, content of nucleic acids, and specific activity of DNA in colonic mucosa, were similar in both high-gastrin and low-gastrin animals and were unchanged from data in unoperated control animals receiving only the carcinogen. Long-term changes in endogenous gastrin concentration are not followed by colonic mucosal tropic effects, and gastrin does not act as a cofactor in dimethylhydrazine-induced carcinogenesis at this dosage.

1,2-Dimethylhydrazine↗
PubMed1977

Alterations in fecal microflora enzymes related to diet, age, lactobacillus supplements, and dimethylhydrazine.

The bacterial enzymes, beta-glucuronidase, azoreductase, and nitroreductase, have been measured in the fecal microflora of rats. The effects of diet, advanced age, Lactobacillus acidophilus supplements, and dimethylhydrazine on these microbial enzymes activities have been determined. The shift from a grain to a meat diet resulted in 1.5--2.5-fold increase in the activity of all three enzymes. Animals over 20 months of age, consuming a meat diet, showed further increases in fecal beta-glucuronidase activity, while the levels of all three microbial enzymes increased in old rats fed a grain diet. Feeding supplement of L. acidophilus significantly lowered the activity of fecal nitroreductase and azoreductase in meat-eating animals, but had no effect on nitroreductase activity in grain-fed animals. Dimethylhydrazine increased the fecal beta-glucuronidase activity in both grain- and meat-fed animals, but the carcinogen had no effect on nitroreductase or azoreductase activity. These findings have relevance to known features of the epidemiology and etiology of large bowel cancer, and suggest certain approaches to prevention.

Aging↗
PubMed1977

Investigations into the metabolism and mode of action of the colon carcinogens 1,2-dimethylhydrazine and azoxymethane.

Colon cancer can be induced reliably in rodents with 1,2-dimethylhydrazine and azoxymethane (AOM). Our studies deal with the mode of action of these compounds and their organotropism. A partial summary of our previous work on the metabolism of 1,2-dimethylhydrazine and its inhibition by disulfiram, carbon disulfide and other thiono-sulfur compounds is presented. On-going studies with AOM-14C indicate that in male F-344 rats, this carcinogen is rapidly metabolized to 14CO2 (37%, 48 hours), and to methylazoxymethanol-14C (MAM) (0.6--1%), which, along with other metabolites, appears in the urine. Pretreatment of rats with phenobarbital or chyrsene increased exhaled 14CO2 to 53% and 65%, respectively. Pretreatment with disulfiram or CS2 causes a complete, although transient, inhibition of exhaled 14CO2, decreases urinary MAM, and increases significantly the levels of unmetabolized AOM in the exhaled air and in urine. Thus, phenobarbital and chrysene appear to stimulate, while disulfiram and CS2 appear to inhibit, the metabolism of AOM. In vitro hydroxylation of AOM to MAM was demonstrated with rat liver homogenates and microsomal fractions. A hypothetical scheme for the endogenous formation of AOM is presented.

Animals↗
PubMed1980

Antigenic changes in nuclear chromatin in 1,2-dimethylhydrazine-induced colon carcinogenesis.

Chromosomal nonhistone protein-DNA complexes prepared from rat colon adenocarcinoma were used to produce tumor specific antisera in rabbits. The antisera reacted specifically in complement fixation tests with chromatins isolated from rat colon tumor and not with those from a number of other rodent tumors and normal tissues, including normal rat colon epithelial cells. Tumor specificity of this antisera was also demonstrated by their cross reactivity with human and mouse colon adenocarcinomas. Immunohistochemical localization of the antigens by the horseradish peroxidase bridge technique demonstrated their presence in the nuclei. The changes in the immunospecificity of the nuclear antigens in chromatin were studied in colon of rats treated with 1,2-dimethylhydrazine. A significant change in the immunospecificity of the chromatin occurred as early as the fourth week after 1,2-dimethylhydrazine treatment was begun.

Adenocarcinoma↗
PubMed1978

Inhibition of the alkylation of nucleic acids and of the metabolism of 1,2-dimethylhydrazine by aminoacetonitrile.

Pretreatment of rats with aminoacetonitrile inhibited the metabolism of [14C]1,2-dimethylhydrazine to 14CO2 and increased the expiration of [14C]-azomethane. Alkylation of nucleic acids following administration of 1,2-dimethylhydrazine was reduced by aminoacetonitrile to 5% of control levels in liver, 11% of control levels in kidney and 43% of control levels in colon.

Acetonitriles↗
PubMed1980

Induction of colon tumors by a single oral dose of 1,2-dimethylhydrazine.

Male Fischer rats were treated at 7 weeks of age with a single oral dose of 1,2-dimethylhydrazine (35 mg/kg). After 1.5 years, the 14 control and 28 treated animals were killed for general autopsy. The incidence of tumor formation in the treated animals was 78.6% as compared to 0% for the control animals. All tumors (1--3/rat) were located in the colon, with the exception of one in the Zymbal's gland of the ear and one in the small intestine. The dosage of 1,2-dimethylhydrazine used in this study is the lowest single oral dose of this carcinogen reported to induce colon tumors.

Administration, Oral↗
PubMed1984

Aldrin epoxidase and dimethylhydrazine demethylase activities in tumorous and non-tumorous tissue of the human colon and rectum.

High activities of aldrin epoxidase and dimethylhydrazine demethylase were found in human colon and rectum mucosa, the first being as high as in human liver biopsy specimens. Comparisons between tumorous (adenocarcinomas) and non-tumorous tissues of the same individuals revealed loss of activities in tumorous specimens. The presence of epoxidizing enzymes and demethylation of the organ-specific colon carcinogen dimethylhydrazine (DMH) in the intestinal muscosa of tumor-bearing patients implicate them with chemical carcinogenesis also in humans.

Adenocarcinoma↗
PubMed2005

Chemopreventive efficacy of ginger, a naturally occurring anticarcinogen during the initiation, post-initiation stages of 1,2 dimethylhydrazine-induced colon cancer.

BACKGROUND: Ginger (Zingiber officinale Rosc) is a natural dietary component, which has antioxidant and anticarcinogenic properties. We investigated the effect of ginger on the initiation and post-initiation stages of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in male Wistar rats. METHODS: Rats were given a weekly subcutaneous injection of DMH (20 mg/kg body weight) in the groin for 15 weeks. Ginger (50 mg/kg body weight/everyday p.o.) was given to the rats at the initiation, post-initiation stages of carcinogenesis. The activity of lipid peroxidation was studied by measuring the formation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and conjugated dienes (CD), and the antioxidant status by measuring superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione-S-transferase (GST), glutathione reductase (GR), reduced glutathione (GSH), vitamins C, E, and A concentrations in the circulation of 1,2-dimethylhydrazine-induced experimental colon cancer. RESULTS: In the presence of a known colon carcinogen, DMH, plasma lipid peroxidation (TBARS, lipid hydroperoxides and conjugated dienes) and cancer incidence were significantly increased whereas enzymic (GPx, GST, GR, SOD and CAT) and non-enzymic antioxidant concentrations (GSH, vitamins C, E, and A) were decreased as compared to control rats. The number of tumors as well as the incidence of cancer was significantly decreased on treatment with ginger. In addition, ginger supplementation at the initiation stage and also at the post-initiation stages of carcinogenesis significantly reduced circulating lipid peroxidation and significantly enhanced the enzymic and non-enzymic antioxidants as compared to unsupplemented DMH-treated rats. CONCLUSIONS: Ginger supplementation suppresses colon carcinogenesis in the presence of the procarcinogen DMH.

1,2-Dimethylhydrazine↗
PubMed1976

Separation of 1,2-dimethylhydrazine metabolites by high-pressure liquid chromatography.

The separation of 1,2-dimethylhydrazine, azomethane, azoxymethane, methylazoxymethanol, methylazoxymethanol acetate, formaldehyde and methanol by high-pressure liquid chromatography on columns of C18/Corasil, muBondapak C18 and Aminex A-27 is described. The separations are highly reproducible and rapid and may be used for kinetic studies. An example of an application of these methods to the analysis of metabolites in rat urine derived from (14C)-1,2-dimethylhydrazine is reported.

Animals↗
PubMed2001

Effect of dietary fiber on the activity of intestinal and fecal beta-glucuronidase activity during 1,2-dimethylhydrazine induced colon carcinogenesis.

The effects of fiber isolated from black gram (Phaseolus mungo) and coconut (Cocos nucifera) kernel on the metabolic activity of intestinal and fecal beta glucuronidase activity during 1,2-dimethylhydrazine induced colon carcinogenesis were studied. The results indicated that the inclusion of fiber from black gram and coconut kernel generally supported lower specific activities and less fecal output of beta-glucuronidase than did the fiber free diet. This study suggests that the fibers isolated from coconut or black gram may potentially play a role in preventing the formation of colon tumors induced by the carcinogen 1,2-dimethylhydrazine by reducing the activity of the intestinal as well as fecal beta-glucuronidase.

1,2-Dimethylhydrazine↗
PubMed1977

Dimethylhydrazine-induced colon tumors in rats fed diets containing beef fat or corn oil with and without wheat bran.

Male rats of the Sprague-Dawley strain were fed semisynthetic diets containing either 20% beef fat or corn oil with and without 20% wheat bran. Half of the animals received four weekly doses and the other half received eight weekly doses of dimethylhydrazine, 30 mg/kg, by intragastric intubation. The percentage of rats with tumors of the colon of all types was significantly higher in animals fed no bran than in those fed bran. Likewise, the percentage of rats with polypoid neoplasms of the colon was higher in rats fed no bran, but there was no significant difference in the percentage of rats with malignant tumors of the colon with respect to the feeding of bran. No significant differences were found between rats fed corn oil and those fed beef fat with respect to either the incidence or the kinds of colon tumors. Malignant tumors of the colon, causing death, occurred earlier in rats fed corn oil as compared to those fed beef fat. The percentage of rats with tumors of the colon and the numbers of tumors per tumor-bearing rat were significantly increased in rats given eight doses of dimethylhydrazine or compared to those given four.

Adenocarcinoma↗
PubMed1990

Protease inhibitor suppression of colon and anal gland carcinogenesis induced by dimethylhydrazine.

In the present study, we examined the ability of chymostatin, a highly specific inhibitor of chymotrypsin, to suppress dimethylhydrazine-induced colon carcinogenesis, and the dose-response relationship for an extract of soybeans containing the Bowman-Birk inhibitor (BBI) to suppress dimethylhydrazine-induced colon carcinogenesis, when added to the diet of mice. Our results showed that: (i) diets containing 0.1% BBI reduced the incidence of adenocarcinomas of the colon approximately 50%, but had no effect on the incidence of squamous cell carcinomas of the anal gland; (ii) the suppressive effect requires protease inhibitor activity, as the autoclaved BBI, in which all protease inhibitory activity has been destroyed, was ineffective at suppressing the incidence of adenocarcinomas; (iii) chymostatin suppressed the incidence of squamous cell carcinomas of the anal gland, but not adenocarcinomas of the colon; and (iv) the growth rates of the animals were the same in each of the experimental groups. Our results indicate that the levels of anticarcinogenic protease inhibitors present in the diets of these animals do not have any adverse effects on the growth or general health of the animals.

Animals↗
PubMed1995

Dairy proteins protect against dimethylhydrazine-induced intestinal cancers in rats.

The impact of different dietary protein sources (whey, casein, soybean, red meat) on the incidence, burden and mass index of intestinal tumors induced by dimethylhydrazine in male Sprague-Dawley rats was assessed. A purified diet (based on AIN-76A) with a fat concentration of 20 g/100 g and other proteins substituted for casein (20 g/100 g) was used. Whey and casein diets were more protective against the development of intestinal tumors than were the red meat or soybean diets, as evidenced by a reduced incidence of rats affected (P = 0.15), fewer tumors per treatment group (burden, P < 0.005), and a reduced pooled area of tumors (tumor mass index) that formed (P = 0.39). Intracellular concentration of glutathione, an antioxidant and anticarcinogenic tripeptide, measured in liver, was greatest in whey protein- and casein-fed rats and lowest in soybean-fed animals (P < 0.001). For other tissues (spleen, colon, tumor) the differences were not significant, although the whey-fed animals had the highest concentrations of glutathione (P = 0.8). Whey is a source of precursors (cysteine-rich proteins) for glutathione synthesis and may be important in providing protection to the host by stimulating glutathione synthesis. A positive correlation was observed between mean fecal fat concentrations for rats in each treatment group and large intestinal tumor burden (r2 = 0.898, P = 0.05). Fecal fat could be involved in aiding initiation and/or promotion of carcinogenesis. Whatever the mechanism(s), dairy proteins, and whey proteins in particular, offer considerable protection to the host against dimethylhydrazine-induced tumors relative to the other protein sources examined.

Animals↗
PubMed1980

Effect of Lactobacillus acidophilus dietary supplements on 1,2-dimethylhydrazine dihydrochloride-induced intestinal cancer in rats.

The epidemiologic patterns of large bowel cancer have implicated a diet high in beef as a risk factor. Another study has shown less colon cancer in Finns than in Danes. Among the possible explanations were the consumption of milk and fermented dairy products and the numbers of lactobacilli in the fecal flora, both of which were higher in the Finns. As a test of these hypotheses, 20 mg 1,2-dimethylhydrazine dihydrochloride/kg body weight was administered for 20 weeks to male inbred F344 rats. Rats consuming a beef diet simulating a "Western" diet had higher rates of colon cancer than did grain-fed rats (83% vs. 31%, respectively). Viable cultures of Lactobacillus acidophilus were fed to rats eating the meat diet; the rats were then challenged with 1,2-dimethylhydrazine dihydrochloride. The colon cancer incidence after a 20-week induction period was lower in the animals receiving the L. acidophilus (40% vs. 77% in controls), but no difference in incidence was discerned after a 36-week period. Thus dietary supplements of L. acidophilus seemed to increase the latency or induction time for experimental colon cancer.

Animals↗
PubMed1978

Effect of hydrazine, isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine on guanylate cyclase activity.

The chemical carcinogen hydrazine is a potent stimulator of guanylate cyclase. In the present investigation we found that three chemical carcinogens structurally related to hydrazine, isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine, decreased guanylate cyclase activity. It is of interest that hydrazine has been shown to increase DNA synthesis whereas isonicotinic acid hydrazide, hydrazine sulfate, and dimethylhydrazine decrease DNA synthesis. The relationship, if any, linking the guanylate cyclase-cyclic GMP system to DNA synthesis and carcinogenesis remains to be explored.

Animals↗
PubMed1997

Changes in the number and apoptosis of epithelial cells in the colorectum of wheat bran-fed rats soon after administering 1,2-dimethylhydrazine.

We investigated the effect of dietary wheat bran (Wb) on colonic tumorigenesis soon after a single administration of 1,2-dimethylhydrazine (DMH). Rats that had been fed on either a fiber-free diet or a 20% Wb diet were injected with 1,2-dimethylhydrazine (20 mg/kg body weight). At 6h, 12h, 1d, 3d, or 7d after the injection, the colorectum was excised for histological analyses. The number of crypt cells more rapidly recovered in the 20% Wb group than in the fiber-free group after its temporary reduction by injection of DMH. At 6h after the DMH treatment, the apoptotic cells were significantly greater in number in the fiber-free group than in the 20% Wb group. In contrast, those in distal colon were significantly fewer in the fiber-free group than in the 20% Wb group at 7d after the treatment. These results suggest that the ingestion of Wb affected the turnover of colonic epithelial cells and would thereby bring about a protective effect against DMH-induced tumorigenesis.

1,2-Dimethylhydrazine↗
PubMed1991

The in vitro and in vivo effects of 1,1-dimethylhydrazine (UDMH) on murine lymphocyte subsets and Ia antigen expression.

1,1-Dimethylhydrazine or unsymmetrical dimethylhydrazine (UDMH) is a highly volatile and reactive compound used primarily as a liquid rocket propellant. Previous studies found UDMH to possess immunomodulatory activity similar to other hydrazine derivatives. Modulation of T lymphocyte subpopulations and Major Histocompatibility Complex Class II or Ia antigen were evaluated as possible mechanisms for this UDMH-induced immunomodulation. Murine lymphoid cell populations were examined by flow cytometry for changes in their cell surface marker percentages or relative number upon exposure to UDMH either in vitro or in vivo. The results show UDMH caused significant suppression of the T helper cell population derived from the thymus at the 75 mg/kg dose in vivo, but did not affect other lymphocyte subpopulations isolated from mesenteric lymph node, spleen or thymus at this or any other dose. In vivo exposure of mice at all doses of UDMH did not significantly alter expression of Ia antigens on adherent cell populations and expression of the Ia antigen following in vitro UDMH exposure was not affected as well. Results indicate that the immunomodulatory effects of UDMH are not mediated by phenotypic alteration of T lymphocyte subpopulations or Ia antigen.

Adjuvants, Immunologic↗
PubMedDate not supplied

The early phase of colon tumorigenesis induced by dimethylhydrazine in ICR mice.

In order to study the influence of fiber supplements on dimethylhydrazine induction of colon tumorigenesis six-week-old CD1 (ICR): Crj mice were injected i.m. at a dimethylhydrazine (DMH) dose 10 mg/kg body weight once weekly for 10 weeks with or without dietary supplementation with 3% polydextrose, lactosucrose or cellulose, or 3% polydextrose and 3% cellulose in combination. There were no significant differences in colon tumor induction among the groups. However, microadenomas were observed 10 weeks after the first treatment of DMH so that this protocol may be useful for studies of the early phase of colon carcinogenesis in mice.

Adenocarcinoma↗