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PubMed1985

Modification by five antioxidants of 1,2-dimethylhydrazine-initiated colon carcinogenesis in F344 rats.

The effects of antioxidants given in the post initiation phase of colon tumor development were investigated in male F344 rats treated with 1,2-dimethylhydrazine (DMH). Animals (20/group) were given s.c. injections of DMH at a dose of 20 mg/kg once a week for four consecutive weeks. One week after the last injection, rats were fed diet containing 5% sodium L-ascorbate (SA), 0.5% butylated hydroxyanisole (BHA), 0.8% ethoxyquin (EQ), 1.0% propyl gallate or 0.5% butylated hydroxytoluene (BHT) for 36 weeks. A control group was fed the basal diet not containing antioxidants. The experiment was terminated 40 weeks after the first injection of DMH and all intestinal tumors were confirmed histologically. SA significantly increased the incidence of adenomas and the number of tumors per rat of the colon (especially of the distal colon). Although EQ and BHT did not affect the number of rats with colon tumors, the number of tumors per rat occurring in the distal colon was significantly increased by EQ while being decreased by BHT. No modification of tumor development was observed with BHA or PG. Thus, modification of tumor development by SA, EQ and BHT was apparent, mainly in the distal colon.

1,2-Dimethylhydrazine↗
PubMed1985

Effect of exogenous beta-glucuronidase on the carcinogenicity of 1,2-dimethylhydrazine in rats: evidence that carcinogenic intermediates form conjugates and act through their subsequent enzymatic release.

Albino, outbred 3-month-old rats were given a single s.c. dose of 1,2-dimethylhydrazine dihydrochloride (DMH; 100 mg/kg) and, 6 or 24 h later, an i.v. dose of bovine liver beta-glucuronidase (3 X 10(4) Fishman units). After this treatment, the incidence of tumours of the large intestine and Zymbal gland, and of cystocholangiomas was similar to that found in rats treated with DMH alone; the incidence of malignancies in various other tissues was considerably higher than that in rats treated only with DMH, especially in animals exposed to beta-glucuronidase 24 h after administration of DMH. beta-Glucuronidase itself had no carcinogenic activity. The broadening of the spectrum of malignant tumours produced in DMH-treated rats by administration of beta-glucuronidase indicates that the carcinogenic effect of DMH may be exerted through formation of comparatively stable conjugates of its metabolites and their enzymic release in target tissues. The approach used in this study could be helpful in investigating the formation of conjugates from other carcinogens.

1,2-Dimethylhydrazine↗
PubMed1987

Sequential histochemical and morphometric studies on preneoplastic and neoplastic lesions induced in rat colon by 1,2-dimethylhydrazine.

The sequential histochemical changes during colon carcinogenesis were studied in male Sprague-Dawley rats given 16 weekly subcutaneous injections of 15 mg 1,2-dimethylhydrazine per kg body wt and serially killed at regular intervals. Cryostat sections were used to study the mucus content of the colonic mucosa with the periodic acid Schiff's reaction, and enzyme histochemical methods were applied to investigate the activity of some key enzymes of carbohydrate metabolism at different stages of carcinogenesis. Enlarged mucus-rich crypts with a marked hypercellularity (149% of control as determined morphometrically) appearing very early during carcinogenic treatment revealed almost normal activities of glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Hyperbasophilic crypts lacking mucus production were observed later and showed a loss of G6Pase, but marked increase of G6PDH and GAPDH activity. Mucus-rich signet ring cell carcinomas showed the same enzymatic pattern as the mucus-rich crypts, whereas mucus-free adenocarcinomas and undifferentiated carcinomas revealed a loss of G6Pase and highly increased G6PDH and GAPDH activities. The results showed that focal changes in polysaccharide content and in the activity of some enzymes of carbohydrate metabolism, as observed in various organs, also accompany the carcinogenic process in the colon. This supports the concept that aberrations in carbohydrate metabolism play an important role during the process of carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1987

Relative activities of thymidylate synthetase and thymidine kinase in 1,2-dimethylhydrazine-induced colon carcinomas in rats.

Thymidylate synthetase (TS) and thymidine kinase (TK) are known to catalyse the methylation of dUMP for the de novo synthesis of dTMP and the phosphorylation of thymidine for the salvage synthesis of dTMP in the pyrimidine pathway, respectively. High TS and TK activities and the existence of TK isozymes have been observed in rapidly proliferating tissues. TS and TK activities in 1,2-dimethylhydrazine (DMH)-induced colon carcinomas in rats increased significantly to 331 and 207% of the activities in normal colon, respectively, and were well correlated inversely (y = -0.93x + 5.24), with a correlation coefficient of -0.787. The colonic TK isozymes were separated into two types by DEAE-cellulose column chromatography. The TK isozyme eluted from the column by the elution buffer alone without NaCl was markedly higher (23.6-fold) in activity in DMH-induced colon carcinoma than in normal control colon and was not affected by deoxycytidine triphosphate. This isozyme, whose mol. wt is 100,000 by h.p.l.c., is thought to be closely involved in rapid DNA replication. These results indicate that early biochemical changes in DMH-induced colon carcinoma in rats may serve as a useful model and provide valuable insight into the mechanisms involved in colonic carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1987

Diallyl sulfide, a flavor component of garlic (Allium sativum), inhibits dimethylhydrazine-induced colon cancer.

Diallyl sulfide, a thioether found naturally in garlic, when given by gavage to C57BL/6J mice inhibited by 74% the incidence and reduced the frequency of colorectal adenocarcinoma induced by 20 weekly injections of 1,2-dimethylhydrazine. This result was predicted from a short-term assay measuring defects in nuclear morphology in mouse colon epithelial cells. This chemical is representative of a class of naturally occurring sulfur compounds with profound pharmacologic activity, one aspect of which may be cancer prevention.

1,2-Dimethylhydrazine↗
PubMed1988

1,2-Dimethylhydrazine carcinogenesis in neonatally androgenized CBA mice.

The aim of this study was to investigate the possible influence of exposure to steroid hormones early in life on the susceptibility of animals as adults to chemical carcinogens. CBA male and female mice received a single subcutaneous injection of 0.5 mg testosterone propionate (TP) in olive oil within 24 h after birth. At the age of 2 months, neonatally androgenized and control mice started receiving weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH). By the end of the experiment, 90% of neonatally androgenized females treated with DMH developed uterine sarcoma against 9% in control females treated with DMH, this difference being attributed to the hyperoestrogenization of androgenized females. In neonatally androgenized males treated with DMH 79% developed pararenal sarcoma and 71% colon tumours versus 25 and 32% respectively of control males treated with DMH.

1,2-Dimethylhydrazine↗
PubMed1988

Target tissue DNA damage in inbred mouse strains with different susceptibility to the colon carcinogen 1,2-dimethylhydrazine.

We have compared liver, kidney and colon DNA damage, as single strand breaks, in mice with different strain-dependent susceptibility to the colon-specific carcinogen 1,2-dimethylhydrazine (DMH). The mouse strains studied were: AKR/J, DBA2 totally resistant; CD1, C57BL/6N moderately susceptible; SWR/J very susceptible to DMH-induced carcinogenesis. DNA breaks were estimated from the elution rate constant (K) according to the alkaline elution technique. At 4 h after carcinogen administration a substantial and comparable DNA damage was found in liver and kidney in all the strains examined. The DNA fragmentation index, however, reached a maximum value at 2 h after treatment in the liver of the most susceptible strain (SWR/J). About 50% of the liver DNA damage detected in all five strains 4 h after DMH administration persisted at 24 h after treatment and was totally repaired at 72 h. Kidney DNA damage decreased in 48 h toward the range of control values. In colon epithelial cells (the carcinogen target tissue) 2 and 4 h after DMH administration the amount of DNA single strand breaks was correlatable with the strain sensitivity to the carcinogen. In the time interval studied (2-72 h after DMH administration) the decrease of colon DNA damage was linear in the resistant strains. In contrast, in the more susceptible strain (SWR/J), the amount of DNA breaks remained high up to 24 h after treatment and returned to background level at 72 h.

1,2-Dimethylhydrazine↗
PubMed2003

Effect of PSC 833, an inhibitor of P-glycoprotein, on 1,2-dimethylhydrazine-induced liver carcinogenesis in rats.

The present study explores the hypothesis that over-expression of P-glycoprotein (Pgp, product of mdr1) is intimately associated with liver cancer development and therefore inhibitors of Pgp should inhibit the development of liver cancer. Accordingly, we determined the effect of PSC833 (PSC), a potent inhibitor of Pgp, on experimental liver carcinogenesis in rats. To study the effects of PSC on liver cancer development, a daily dose of 30 mg PSC/kg body wt (PSC30) was chosen based on an initial dose-response experiment. Accordingly in experiment 1, PSC30 was fed to rats initiated by 1,2-dimethylhydrazine coupled with two-thirds partial hepatectomy and promoted for 22 weeks with 1% dietary orotic acid. Surprisingly, in contrast to our earlier observations in rats without hepatic nodules, in rats bearing hepatic nodules, PSC30 was found to be toxic. Because of this, PSC30 diet was discontinued after 5 weeks and the rats were transferred to basal diet (BD). The rats were killed 10 and 25 weeks thereafter. Cumulative results indicate that PSC30 exhibited a 40% decrease in the incidence of hepatocellular carcinoma (HCC; 15 of 18 in the BD group compared with eight of 17 in the PSC30 group; P = 0.08) coupled with significant reduction of tumor multiplicity (54%; P < 0.05) and tumor burden (61%; P < 0.005) compared with controls. In experiment 2, 15 mg PSC/kg body wt (PSC15) was fed for 20 weeks to rats similarly initiated and promoted for 35 weeks. PSC15 inhibited the incidence of HCC by 75% (four of four in the BD group compared to one of four in the PSC30 group; P = 0.15) and significantly reduced tumor burden by 55% (P < 0.05). The lack of statistical significance of inhibition on tumor incidence reflects the small sample size. Taken together the results indicate a possible intrinsic role for Pgp in liver cancer development and introduce another promising unexplored therapeutic approach in liver cancer treatment.

1,2-Dimethylhydrazine↗
PubMed1985

Plasma amino acids and excretion of protein end products by mice fed 10 or 40% soybean protein diets with or without dietary benzo[a]pyrene or 1,2-dimethylhydrazine.

The effects of two carcinogens benzo[a]pyrene (BP) and symmetrical 1,2-dimethylhydrazine dihydrochloride (DMH), on plasma amino acid concentrations and on excretion of lipids and nitrogenous metabolites were studied in 7- to 8-wk-old male and female B6C3F1 mice. BP and DMH were fed at concentrations of 0.3125 and 0.0225 g/kg, respectively, in purified diets containing 10 or 40% soybean protein. Nutritional balances were measured over a 7-d period after 7 d of acclimatization. Females excreted less urea and more NH3 than males. Urinary urea-nitrogen, NH3, allantoin, uric acid and total urinary nitrogen were consistently higher in mice fed 40% protein than in those fed 10% protein. The increases in total and NH3 nitrogen paralleled the increase in nitrogen intake. Nitrogen of urea rose more, while that of allantoin and uric acid rose less, than nitrogen intake. Fecal lipid excretion, as a percentage of intake, was consistently higher in mice fed the 40% protein diets than in mice fed 10% protein. Plasma glycine and branched-chain amino acids were higher, but citrulline was lower, when the 40% protein diet was fed. Body weight gain was higher when the 10% protein diet was fed with BP than without it, but BP made no apparent difference in weight gain when the 40% protein diet was fed. BP interacted with dietary protein to influence the excretion of nitrogenous metabolites. In addition, BP feeding produced numerous BP X sex and BP X protein interactions for plasma amino acid concentrations. Compared to controls, feed intake and weight gain were, respectively, 8 and 61% lower in DMH-fed animals during wk 1, but no differences in intake or weight gain were found during wk 2. In contrast to BP, DMH had no significant effects on urinary or fecal nitrogen metabolites, except that urinary uric acid (relative to nitrogen intake) was 9% higher in DMH-fed mice than in controls. DMH-fed mice had 43% higher serum glutamate and 6% lower glutamine than controls.

1,2-Dimethylhydrazine↗
PubMed1985

Effect of dietary selenium deficiency on incidence and size of 1,2-dimethylhydrazine-induced colon tumors in rats.

Torula yeast diets deficient (less than or equal to 0.02 ppm) in selenium (Se) and a control diet supplemented with sodium selenite (0.1 ppm Se), were fed to 52 male Sprague-Dawley rats per diet for 23 wk following weaning. 1,2-dimethylhydrazine (DMH) was administered (20 mg/kg body weight) in 20 weekly i.p. injections after 3 wk of feeding. After 23 wk, 67% of the rats fed the Se-deficient diet had intestinal adenocarcinomas versus 63% on the 0.1 ppm Se diets. Diet also had no effect on the number or size of tumors per tumor-bearing animal or on the location of the tumors within the colon. The effects of Se deficiency on the hematological variables of white blood cell count, hematocrit, serum urea nitrogen and cholesterol concentrations were examined. Serum urea nitrogen levels were lower in Se-deficient DMH-treated rats (9.6 +/- 0.7 vs. 13.7 +/- 0.9 mg/dl, P less than 0.01) and serum cholesterol was higher in Se-deficient DMH-treated animals (69.0 +/- 5.5 vs. 50.7 +/- 3.9 mg/dl, P less than 0.05). Body weights of the Se-depleted group were lower in the DMH-treated animals (P less than 0.01) although food consumption did not differ. Controls without DMH did not show differences due to Se status for any variable examined. Se deficiency appears to affect DMH toxicity but nutritional adequacy (0.1 ppm Se) does not inhibit tumor development. The results of this study do not support the belief that Se deficiency enhances colon carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed1991

Dietary selenium and antioxidant status: toxic effects of 1,2-dimethylhydrazine in rats.

Weanling male Sprague-Dawley rats were used to determine whether the mechanism of the previously reported toxicity of 1,2-dimethylhydrazine (DMH) in selenium-deficient rats was related to a diminished capacity for detoxification of reactive oxygen species via glutathione peroxidase (GSH-Px) as well as by other known pathways of detoxification, including catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) and levels of glutathione (GSH). A 3 x 3 factorial experimental design was used to examine the acute effects of DMH treatment (0, 10 and 20 mg/kg body weight) interacting with dietary Se levels (less than 0.02, 0.1 and 0.5 mg/kg diet as sodium selenite). Animals were maintained on the test diets for 4 wk prior to challenge with DMH. Preliminary kinetics studies indicated the most appropriate time to examine antioxidant status was 3 h after DMH injection. At that time, livers and colons were analyzed for tissue levels of GSH-Px, CAT, SOD, GST and GSH. Data analysis demonstrated that Se deficiency impaired the ability of both liver and colon to mount an induced detoxification response to the acute oxidative stress generated by DMH challenge and may explain the toxicity of DMH in Se-deficient rats.

1,2-Dimethylhydrazine↗
PubMed1991

Effect of dietary calcium on colon carcinogenesis induced by a single injection of 1,2-dimethylhydrazine in rats.

The purpose of this study was to determine if high levels of dietary calcium could inhibit the induction of colon tumors in rats injected with a single dose of 1,2-dimethylhydrazine (DMH). Rats were given a single subcutaneous injection of DMH (200 mg/kg body weight) 2 wk before they were fed purified diets containing 5% fat and four different levels of calcium (as calcium gluconate). After 8 mo, the following incidences of colon tumors (total) were seen: 0.2% Ca, 56%; 0.5% Ca [National Academy of Sciences/National Research Council (NAS/NRC) recommended level], 75%; 1.0% Ca, 61%; 2.0% Ca, 41%. Thus, rats fed calcium at levels above or below the NAS/NRC recommendation had lower tumor incidences. The total tumor incidence and the incidence of adenocarcinomas (with or without invasion) were not significantly affected by calcium, but the incidences of benign adenomatous polyps and of distal colon tumors were significantly affected. Autoradiographic examination of [3H]thymidine-treated rats revealed that the level of calcium did not significantly alter the cell kinetic indices in the distal colon. In the proximal colon, however, the 0.2% Ca group had a significantly larger proliferative zone, with significantly more labeled cells present at the bottom of the colon crypt. Mineral analysis of tibias and serum samples revealed that rats fed higher levels of calcium had lower bone Fe and serum Mg contents, but no significant trends were seen for Ca, P, Zn or Cu. Therefore, increasing or decreasing the calcium content above or below the NAS/NRC recommendation (supplemented to low fat diets) during the promotional phase of colon carcinogenesis altered the tumor incidence, but the effect was confined to the distal colon and to benign adenomatous polyps.

1,2-Dimethylhydrazine↗
PubMed1992

Rat colonic antioxidant status: interaction of dietary fats with 1,2-dimethylhydrazine challenge.

The polyunsaturated fatty acid composition of dietary fat has been associated with increased oxidant stress in tissues. We previously showed that antioxidant mechanisms in colon mucosa are affected by dietary fat. In this study, the colonic antioxidant response to treatment with the colon-specific carcinogen 1,2-dimethylhydrazine (DMH) was determined. Sprague-Dawley rats were fed one of four AIN-76A-based diets with varied fat content. The basal diet contained 5% corn oil, the menhaden oil diet contained 19% menhaden oil and 1% corn oil, the corn oil diet contained 20% corn oil and the beef tallow diet contained 19% beef tallow and 1% corn oil. Animals were given one or two intraperitoneal injections of either DMH (20 mg/kg) or 1 mmol/L EDTA. Homogenates of colon mucosa were assayed to determine activity of catalase, glutathione peroxidase, total superoxide dismutase, manganese superoxide dismutase, glutathione reductase and glutathione-S-transferase, as well as total glutathione concentration, thiobarbituric acid-reacting substances and nuclear aberrations. Total glutathione concentration was greater in rats fed all diets following two injections of DMH, whereas glutathione reductase activity remained unchanged relative to controls. Lipid peroxidation was highest in the group fed menhaden oil; nuclear aberrations were greatest in the corn oil-fed group. In conclusion, both type and amount of dietary fat modified the response of colon tissue to genotoxic challenge, but none of the diets seemed more protective than the others.

1,2-Dimethylhydrazine↗
PubMed1993

Influence of dietary calcium and vitamin D on colon epithelial cell proliferation and 1,2-dimethylhydrazine-induced colon carcinogenesis in rats fed high fat diets.

We investigated whether increased levels of dietary calcium and vitamin D could inhibit colon carcinogenesis in rats injected with a single dose of 1,2-dimethylhydrazine. Rats were given a single subcutaneous injection (200 mg/kg body wt) 2 wk before they were fed purified diets containing 20% fat for 32 wk. Diets contained one of three levels of calcium (5, 10 or 15 g/kg diet) as calcium gluconate and one of three levels of vitamin D (0.025, 0.05 or 0.1 mg/kg diet) as cholecalciferol in a 3 x 3 factorial design. Rats receiving the highest level of vitamin D had greater plasma concentrations of 25-hydroxy-vitamin D. Autoradiographic examination of [3H]thymidine-treated rats demonstrated that a higher dietary level of calcium as well as higher levels of vitamin D significantly affected cellular kinetic indices. The total tumor incidence and tumor incidence in the distal colon was 45% lower in rats fed the highest level of both calcium and vitamin D compared with the other eight groups, although this decrease was not statistically significant (P = 0.12). The possible importance of these observations is discussed.

1,2-Dimethylhydrazine↗
PubMed1989

Induction of renal tumors in cynomolgus monkeys (Macaca fascicularis) by prenatal exposure to 1,2-dimethylhydrazine.

Nephroblastomas were induced at an early age in two of six cynomolgus monkeys by prenatal exposure to 1,2-dimethylhydrazine. In one, the tumor of the right kidney had metastasized into the lower lobes of the lungs. By their histologic structure, development, and clinical course, the induced nephroblastomas were analogous to the Wilms' tumors often found in children.

1,2-Dimethylhydrazine↗
PubMed1995

High resolution rodent bone marrow micronucleus assays of 1,2-dimethylhydrazine: implication of systemic toxicity and individual responders.

1,2-Dimethylhydrazine (DMH) is confirmed as active in male CBA mouse bone marrow micronucleus (MN) assays conducted at non-toxic dose-levels between 25 and 45 mg/kg. Previous reports of the activity of DMH in rodent bone marrow MN assays are reviewed. By the design of the present experiments it has been possible to confirm the advice offered by the United Kingdom Environmental Mutagen Society (UKEMS) that once 2000 polychromatic erythrocytes have been assessed per animal, the use of larger animal group sizes becomes the critical means to increase assay sensitivity. Also, the use of historical control data is shown to enhance assay sensitivity at low dose-levels by enabling recognition of individual animals responding to the test chemical. These outliers are seen before the group mean MPE value has been increased enough to attain group statistical significance. It is concluded that careful consideration of test data, within the context of concurrent and historical control data, is sufficient to discern activity in the assay.

1,2-Dimethylhydrazine↗
PubMed1996

Mutagenicity and toxicity of the DNA alkylation carcinogens 1,2-dimethylhydrazine and azoxymethane in Escherichia coli and Salmonella typhimurium.

DNA alkylating agents such as 1,2-dimethylhydrazine (SDMH) and azoxymethane (AOM) are potent carcinogens and are widely used to induce colon tumors in experimental animals. However, standard bacterial mutagenesis assays have failed to detect the mutagenic effects of these chemicals. Using derivatives of a set of Escherichia coli test strains developed by Cupples and Miller (Proc. Natl. Acad. Sci. USA, 86, 5345, 1989), we hve demonstrated that under two conditions, SDMH and AOM induced point mutations by several-fold in a dose-dependent manner: (i) of six possible base substitutions, they only induced GC-->AT transitions; and (ii) the cells must be deficient in O6-methylguanine (O6MeG) DNA methyltransferase (MTase) activity. SDMH and AOM up to 200 microg/ml were unable to induce His+ revertants in a Salmonella Ames test strain TA1535 (GC-->AT); however, in the absence of mammalian S9 extract, His+ revertants increased up to 55-fold upon treatment of an isogenic Salmonella strain deficient in MTase activity. These results indicate that SDMH and AOM are indeed bacterial mutagens and that lesions induced by them are the target of DNA repair MTases, which probably include mutagenic and carcinogenic lesions such as O6MeG. Furthermore, variable responses of bacterial species to SDMH- and AOM-induced mutagenicity suggests a difference either in the metabolism of potential mutagens or in the repair of specific lesions. Since O6MeG is not only a mutagenic lesion but also a lethal lesion if left unrepaired, we compared the mutagenicity and toxicity of SDMH and AOM with an SN-type methylating carcinogen. N-methyl-N'-nitro-N-nitrosoguanidine, and conclude that SDMH and AOM are weak bacterial mutagens.

1,2-Dimethylhydrazine↗
PubMed1997

Enhanced restriction site mutation (RSM) analysis of 1,2-dimethylhydrazine induced mutations, using endogenous p53 intron sequences.

The restriction site mutation (RSM) assay was used to study the mutational sensitivities of three target regions of the murine p53 gene. The non-coding intron 6 target region was compared with the coding regions exon 4 and exon 5 with respect to their relative sensitivity to the induction of mutations by 1,2-dimethylhydrazine (DMH). Our results demonstrated that the majority of induced mutations detected were in the intron 6 gene region. A total of 15 enzyme-resistant restriction sites were detected in DMH treated mice, nine of these in the intron 6 region, four in the exon 4 region and two in the exon 5 region. The elevated sensitivity of the intron 6 region was exemplified by our detection of spontaneous mutations in this region; two resistant restriction sites were detected in untreated animals. No spontaneous mutations were detected in either of the exon sequences studied here, nor have any been detected in exon targets in our previous in vivo RSM analyses. The mutations induced by DMH were mostly GC-->AT transitions, as were the spontaneous mutations identified. The mutation frequencies calculated by the inclusion of a mutant internal standard (MIS) in the RSM method, revealed that the non-coding intron 6 region and the exon 4 region had a 10-fold higher mutation frequency than the exon 5 region. This heterogenous distribution of mutations and their differential mutation frequencies, were probably a consequence of the greater selection in the coding regions in p53 function. However, the actual mechanism of differential mutation induction is, as yet, to be defined.

1,2-Dimethylhydrazine↗