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PubMed1989

Oxidative metabolism of 4-hydroxy-2,3-nonenal during diethyl-nitrosamine-induced carcinogenesis in rat liver.

In some chemically-induced hepatomas and in cultured transformed cells the aldehyde dehydrogenase activity was found increased in the presence of aromatic aldehyde as substrate. We studied this enzyme during diethyl-nitrosamine carcinogenesis in rat liver by using an aliphatic aldehyde, 4-hydroxynonenal, as substrate. 4-Hydroxynonenal is an important product of lipid peroxidation. The NAD- and NADP-dependent aldehyde dehydrogenase of the cytosolic fraction and the NADP-dependent aldehyde dehydrogenase of the microsomes show higher values in nodules and hepatoma than in normal liver. These results suggest that increased aldehyde dehydrogenase, when 4-hydroxynonenal is used, can be considered a marker of the neoplastic process, in the same way as the level of aldehyde dehydrogenase increased in presence of aromatic aldehyde.

Aldehyde Dehydrogenase↗
PubMed1991

Lack of synergism in rat urinary tract carcinogenesis between prior uracil treatment and N-butyl-N-(4-hydroxybutyl)-nitrosamine administration.

Combination effects of sequential treatment with uracil prior to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) with regard to carcinogenesis in the urinary bladder and renal pelvis were investigated in male F344 rats. Uracil was administered for 15, 10 or 5 weeks followed by BBN for 23 weeks, the total observation time being 40 weeks. Carcinoma(s) and papilloma(s) were induced in the urinary tract by the 15-week uracil treatment independent of subsequent BBN administration. It was concluded that uracil administration prior to BBN treatment is not associated with any synergistic effects, although both uracil and BBN alone exerted carcinogenicity.

Animals↗
PubMed1994

Influences of aging and sex on renal pelvic carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine in NON/Shi mice.

Influences of aging and sex on renal pelvic carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined in 6-, 15 -and 45-week-old male and female NON/Shi mice. Histopathological examination revealed an age-related shortening of induction time for renal pelvic carcinomas in males, although actual incidences did not increase. The histological patterns of carcinomas induced in both renal pelvis and urinary bladder demonstrated male mice to be more prone to develop transitional cell carcinomas, while squamous cell carcinomas were more likely to arise in females. Moreover, the sex factor appeared to influence the progression of both renal pelvic and urinary bladder carcinomas.

Aging↗
PubMed1996

p53 mutations in transitional cell carcinomas of the urinary bladder in rats treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine.

Involvement of p53 gene alterations has been demonstrated in a variety of human neoplasias including urinary bladder carcinomas. N-Butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced urinary bladder carcinogenesis models in rodents have been widely used to study carcinogenic processes in this organ. In the present study, transitional cell carcinomas induced in the urinary bladders of male F344 rats treated with 0.05% BBN for 16 or 32 weeks and then sacrificed at experimental week 32 were analyzed for mutational changes in the p53 and H-ras genes by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and subsequent DNA sequencing. The total p53 mutation incidences were 3/10 (30%) and 8/12 (66.7%) in rats treated with BBN for 16 weeks followed by 16 weeks' non-treatment, or in rats treated with BBN for 32 weeks, respectively, while the H-ras mutation incidences were 0/10 (0%), and 1/12 (8.3%), respectively. The present results indicate that mutations in the p53 gene might be involved in the process of urinary bladder carcinogenesis by BBN as part of a multistep pathway. However, considering the decreasing tendency in lesions with p53 mutations after stopping BBN administration, a p53 mutation alone would not appear to be sufficient to give a marked selective advantage to mutant cells. No evidence of H-ras mutation involvement was gained even for the late course of rat urinary bladder carcinogenesis.

Animals↗
PubMed1994

Amrita Bindu--a salt-spice-herbal health food supplement for the prevention of nitrosamine induced depletion of antioxidants.

Ayurveda, practised in India, identified a large number of plant components to be used in the diet for the prevention or the delayed development of degenerative disorders. They include some of the commonly used spices, namely pepper and ginger. The Materia Medica includes both naturally occurring and artificially produced salts, as a partial substitute for common salt. Health promoting herbs and spices which are classified pharmacologically as rejuvenating, nourishing, invigorating, cleansing, wound-healing, etc., are used as food additives. Amrita Bindu is a salt-spice-herbal mixture based on these principles and was tested for its effect in maintaining antioxidant defense systems in blood and liver when exposed to a carcinogenic nitrosamine, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Amrita Bindu supplementation prevented MNNG induced depletion of the antioxidant enzymes and the scavenger antioxidants glutathione and vitamins A, C and E. Amrita Bindu provides protection against free radical and reactive oxygen species induced tissue lipid peroxidation and the resultant tissue degeneration.

Animals↗
PubMed1990

The kinetics of cellular proliferation in rat urinary bladder treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The cellular proliferation of the bladder epithelium was determined sequentially in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). The incorporation of bromodeoxyuridine (BrdUrd) into the DNA synthesis phase was determined by an in vitro labeling technique. The percentage of labeled cells was expressed as the labeling index (LI). The average LI values in normal subjects and cancer-bearing subjects were 5.1(%) and 24.2(%) respectively. With the transition of the bladder epithelium from simple hyperplasia to cancer, the LI values of the bladder epithelium were increased. Cases of papillary or nodular (PN) hyperplasia were divided into two types according to the localization of the BrdUrd-labeled cells. The LI in PN hyperplasia was 12.4(%); the difference from cancer was significant. In another experiment, the effect of partial cystectomy on bladder tumors was examined. The group with partial cystectomy showed increases in grade and stage of cancer, and the LI of cancer was more than that in the group without partial cystectomy. The results indicate that partial cystectomy may play a role as promotor for bladder tumors. The current study may be of more practical value than is the conventional one for investigating the histogenesis and progression of human bladder cancer.

Animals↗
PubMed1988

Effect of continuous intravesical infusion of low-concentrated mitomycin-C on bladder carcinogenesis in rats treated with N-butyl-N-4-hydroxybutyl-nitrosamine.

In the first experiment, histological changes of urinary bladder after long-term transvesical catheterization were evaluated in normal rats. No malignant changes of the bladder epithelium were detected in the two and four-week catheterization groups. However incidences of papilloma and papillary carcinoma developed in three of the five rats (60%) in the eight-week group. In a second experiment the therapeutic effect of continuous or intermittent administration of MMC on bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. MMC at a total dose of four mg. was administered for two weeks in both therapeutic groups. Continuous infusion was performed transvesically using an osmotic pump and a silicone catheter, on the basis that preliminary examination revealed the urinary delivery rate of MMC was constant for two weeks. In the intermittent group, MMC solution was instilled transurethrally with a venural catheter twice a week. The continuous infusion of low concentrated MMC reduced significantly (p less than 0.02) the incidence of tumor development in spite of extended catheterization (for eight weeks) into the bladder. However, the intermittent instillation of high concentrated MMC hardly inhibited the development of bladder tumors. We should consider the optimal concentration and time of a drug in intravesical chemotherapy based on the above findings.

Administration, Intravesical↗
PubMed2003

Inhibitory effects of 2-mercaptoethane sulfonate and 6-phenylhexyl isothiocyanate on urinary bladder tumorigenesis in rats induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effects of 2-mercaptoethane sulfonate (MESNA) and phenethyl and 6-phenylhexyl isothiocyanates (PEITC and PHITC) on urinary bladder tumorigenesis were investigated in Wistar rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN). A total of 190 male rats were divided into eight groups. Animals in groups 1, 3 and 4 were administered BHBN in drinking water (0.025%) and group 2 rats were given 0.025% BHBN plus 0.05% MESNA solution for 15 weeks. Rats in groups 3 and 4 were fed a diet supplemented with PEITC or PHITC at a dose level of 0.5 micromol/g for 16 weeks starting 1 week prior to the BHBN treatment. Rats in groups 5-7 served as MESNA, PEITC or PHITC alone controls. Group 8 served as a non-treatment control. The chromatographic profile of drinking water for group 2 animals indicated no chemical interaction between BHBN and MESNA. The incidences of papillomas in the bladder and total bladder tumors including transitional cell carcinomas were significantly (P<0.01) reduced in group 2 as compared to that in group 1. The multiplicities of papillomas or total bladder tumors were significantly (P<0.01) lower in group 2 and 4 rats treated with MESNA and PHITC, respectively, than in group 1 rats. The PEITC treatment, however, did not affect the BHBN-induced bladder tumorigenesis. No bladder tumors were found in animals of groups 5-8. The results in the present study clearly indicate that both MESNA and PHITC are potent chemopreventive agents against bladder tumor development in rats induced by BHBN.

Animals↗
PubMed1997

p53 gene mutation in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder tumors and N-methyl-N-nitrosourea-induced colon tumors of rats.

We analyzed p53 mutations in 17 N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder transitional cell carcinomas (TCCs) with or without areas of squamous cell carcinoma (SCC) of Long-Evans Cinnamon (LEC) and F344 rats, and in 7 N-methyl-N-nitrosourea-induced colon adenocarcinomas of LEC rats by polymerase chain reaction-single strand conformation polymorphism analysis and DNA sequencing. Of these bladder tumors, one TCC with moderately differentiated SCC had a T to G transversion mutation at codon 141, leading to a Val to Gly amino acid change. No p53 mutation was found in colon adenocarcinomas. Thus a p53 gene mutation seems infrequent in these rat bladder and colon carcinogenesis models even in the late stage.

Animals↗
PubMed1998

Infrequent involvement of microsatellite instability in urinary bladder carcinomas of the NON/Shi mouse treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

Variation in the frequency of microsatellite instability (MSI) has been reported in different kinds of human malignant tumors, with less than one-third of invasive urinary bladder carcinoma cases estimated to be affected. Here we investigated the MSI for 27 microsatellite sequences in invasive urinary bladder carcinomas of the NON/Shi mouse induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. A total of 28 urinary bladder carcinomas of both transitional cell and squamous cell types were studied. All were invasive (greater than pT3) and high-grade and 10 of them had metastasis. Only two (11%) of 18 primary bladder carcinomas without metastasis foci showed alterations in one or two loci. None of 10 pairs of urinary bladder carcinomas and metastasis foci demonstrated any alterations. In conclusion, MSI which represents a defect in the DNA mismatch repair system is infrequent and therefore unlikely to be a critical step in genesis of invasive mouse urinary bladder carcinomas.

Animals↗
PubMed1997

Lack of involvement of p53 gene mutations in N-methyl-N-nitrosourea-induced bladder tumor progression in N-butyl-N-(4-hydroxybutyl)nitrosamine-treated rats and no suppression by indomethacin.

The relevance of p53 mutations to rat bladder cancer progression induced by a single injection of N-methyl-N-nitrosourea (MNU) and the chemopreventive effects of indomethacin (IM) were investigated in male F344 rats, initially given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at a dose of 500 ppm in the drinking water for 10 weeks. The animals were subsequently treated with a single intraperitoneal injection of MNU at a dose of 50 mg/kg b.w. at week 20. A subgroup was then given IM dissolved in the drinking water at a concentration of 20 ppm for 20 weeks. The experiment was terminated at week 40 when transitional cell carcinomas (TCC) were observed in all animals given BBN, regardless of the administration of MNU and/or IM (incidences ranged from 80 to 100%). The extent of invasion was significantly greater with the additional MNU treatment but no inhibitory effects of IM were noted. A low frequency of p53 mutations was detected without relation to the extent of tumor invasion. Thus, only two mutations were found, one in a Ta and the other in a T1 carcinoma. The present study thus demonstrated that p53 mutations are not involved in MNU-induced progression in rat urinary bladder cancers, suggesting that they are not critical for malignancy.

Animals↗
PubMed1999

Enhancement of urinary bladder carcinogenesis in nullizygous p53-deficient mice by N-butyl-N-(4-hydroxybutyl)nitrosamine.

We recently reported p53 mutations to be frequent in mouse invasive urinary bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-deficient mice and their littermates were treated with the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary bladder carcinogenesis but not development of other tumors in the nullizygous p53-deficient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild-type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a significant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary bladder carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations.

Animals↗
PubMed1999

Promoting effects of intravesical instillation of saline on bladder lesion development in rats pretreated with N-butyl-N-(4-hydroxybutyl) nitrosamine are inhibited by bacillus Calmette-Guerin.

The promoting effects of intravesical instillation of saline and the efficacy of bacillus Calmette-Guerin (BCG) for prophylaxis of bladder carcinogenesis were assessed. Rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 10 weeks; they were then given 6 weekly intravesical instillations of BCG, saline or distilled water starting 1 week or 15 weeks after the BBN treatment. At 32 weeks, both the incidences and numbers of bladder cancers were elevated in animals receiving the saline. An exception was the early phase BCG group. Significant increases in tumor size were also noted for the saline, but not the distilled water group. The results indicate that intravesical instillation of saline promotes urinary bladder carcinogenesis. However, the inhibitory influence of BCG was suggested if administered at the early, but not the late phase, of carcinogenesis.

Animals↗
PubMed2000

Potential nitrite scavengers as inhibitors of the formation of N-nitrosamines in solution and tobacco matrix systems.

The ability of 20 compounds, all but one tobacco constituents, to inhibit the formation of tobacco-specific N-nitrosamines (TSNA) was investigated in buffer and detergent solution and in tobacco midrib and lamina systems. In solution at pH 5.5, ascorbic acid and the phenolic acids caffeic and ferulic acid were the most potent inhibitors of the reaction between nornicotine and nitrite, with nearly complete inhibition at molar ratios test compound/nitrite > 1:1. Also, cysteine > dihydrocaffeic acid > protocatechuic acid approximately catechin acted as strong inhibitors with >90% inhibition at a ratio of 3:1. Lower inhibitions were observed with chlorogenic acid > p-coumaric acid > sclareol > serine. Rutin showed an inhibition of 34% at a ratio of 0.1:1. Sclareol, alanine, proline, and serine did not significantly affect the N-nitrosonornicotine (NNN) formation. alpha-Tocopherol and glutathione enhanced NNN formation at pH 5.5 but were inhibitors at pH 3. Cinnamic acid, vanillic acid, eugenol, and esculin enhanced NNN formation. Increased NNN formation was also observed for dihydrocaffeic acid, chlorogenic acid, protocatechuic acid, and catechin at a less-than-equimolar ratio of test compound to nitrite. The tobacco matrix experiments were performed with air-cured, ground tobacco midrib and lamina. Caffeic acid, ferulic acid, dihydrocaffeic acid and catechin were potent inhibitors of the formation of TSNA in the midrib as well as in the lamina. Also protocatechuic acid, glutathione, ascorbic acid, p-coumaric acid, chlorogenic acid and cysteine were inhibitors, while alpha-tocopherol and rutin inhibited the reaction in the midrib but not in the lamina. Cinnamic acid, vanillic acid, eugenol, alanine, proline and serine showed small effects only. The molar ratio of secondary alkaloid(s)/nitrite in the test systems were 0.1:1 (solution), approximately 0.25:1 (midrib), and approximately 1:1 (lamina) and is most likely the major contributor to the observed order of inhibition potency (solution > midrib > lamina) of the test compounds. The vicinal phenolic hydroxyl groups of polyphenols and the simultaneous presence of a phenol group and an olefinic bond in hydroxycinnamic acids were the most characteristic structural elements of the potent inhibitors.

Free Radical Scavengers↗
PubMedDate not supplied

A kinetic model of the cell culture cytotoxicity of metabolically activated agents: N-methyl-N-(acetoxymethyl)nitrosamine, methylnitrosourethane, and (methylazoxy)methanol acetate.

The activity of three metabolically activated methylating agents, N-methyl-N-(acetoxymethyl)nitrosamine (DMN-OAc), methylnitrosourethane (MNUT), and (methylazoxy)methanol acetate (MAM-Ac), were determined in cell culture by using a P388 cell growth rate inhibition assay. Experiments were conducted with normal P388 cells in Fischer's medium and under conditions in which the esterase-mediated activation was modified by pretreating cells with the irreversible esterase inhibitor paraoxon and by adding acetylcholinesterase to the medium. Inhibition of intracellular esterase had a much greater effect on activity than did addition of enzyme to medium. These experiments provided data that were used to assess the utility of kinetic models as a means to gain a more detailed understanding of the cytotoxicity process in cell culture. Growth rate inhibition was related to the amount of intracellular alkylation resulting from formation of metabolic intermediates and their subsequent chemical reaction to form methyldiazonium ion and methylation products by using kinetic rate laws and measured rate constants. The model is applicable to systems that form unstable metabolites that can, in part, partition between the cell volume and incubation medium. When growth rate inhibition effects were related to cumulative intracellular alkylation [P], the ED50 values were the same for all three agents and for three previously reported chemically activated methylating agents, N-methyl-N-nitrosourea, streptozotocin, and N-methyl-N'-nitro-N-nitrosoguanidine, which are also thought to act through the methyldiazonium ion. This observation is consistent with a growth rate inhibition effect of the methyldiazonium ion that reflects the intrinsic activity of this species that is independent of the precursor molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1992

Normal human breast xenografts activate N-nitrosodimethylamine: identification of potential target cells for an environmental nitrosamine.

Normal human breast tissue maintained as xenografts in female Balb/c (nu/nu) athymic mice is capable of metabolising N-nitrosodimethylamine (NDMA) to active intermediates that will react with DNA. Administration of NDMA to mice with slow-release implants of 17 beta-oestradiol which provide human physiological (luteal phase) circulating oestrogen levels and increase cell proliferation in the xenograft (Laidlaw et al., 1992), leads to an apparent increase in the extent of reaction with DNA compared to controls without oestrogen implants. In mice with oestrogen implants, measurements of the amounts of the promutagenic lesion, O6-methyl-2'-deoxyguanosine formed in DNA clearly indicated a dose related increase in the extent of reaction. Detection of O6-methyl-2'-deoxyguanosine using immunohistochemical procedures revealed that the nuclei of cells of the glandular epithelium, supportive tissue and adipose tissue, in decreasing order of prevalence, were positively stained for the presence of this DNA lesion. Epithelial cells, which are the putative target cells for carcinogenesis in the breast, are therefore prone to promutagenic damage as a result of exposure to an environmental nitrosamine.

Animals↗
PubMed1999

Inhibition of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats by green tea.

BACKGROUND: Recently, the anticarcinogenic effects of green tea have been studied in sites other than the urinary tract. The present study examined the inhibition by green tea of vesical tumors induced in rats by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). METHODS: In the first series of experiments, 0.05% BBN was added to the drinking water of rats and remained present for 5 weeks. In one experiment, six groups of animals received either tap water, green tea, matcha, hojicha, oolong tea or black tea from week 6. In a second experiment, three groups of rats received either tap water, green tea extract or powdered green tea mixed into a pellet diet from week 6. In a third experiment, five groups of rats were fed a pellet diet with addition of either 0, 0.15, 1.5 or 3.0% powdered green tea from week 6. All rats were killed and examined at 40 weeks. RESULTS: Green tea, particularly green tea leaves, dose-dependently inhibited the growth of BBN-induced urinary bladder tumors when given after the carcinogen. CONCLUSIONS: Green tea may inhibit bladder tumor growth.

Animals↗
PubMed2003

Preventive effects of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rat by green tea leaves.

BACKGROUND: Recently, the anticarcinogenic effects of green tea have been studied in sites other than the urinary tract. Although the incidence of bladder cancer has increased, responses to therapy have been limited. The present work examined the preventive effects of green tea against bladder tumors induced in rats by the carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine(BBN). METHODS: From week 5 to week 9, all the groups were exposed to 0.05% BBN in the drinking water for 5 weeks. Rats were divided into four groups. Group 1 was fed a CE-2 diet and tap water for the entire experimental period and served as the control group. Group 2 was fed the green tea leaves after carcinogen exposure. Groups 3 and 4 received green tea leaves before carcinogen exposure. All rats were killed and examined at 44 weeks. RESULTS: Green tea leaves prevented the growth of BBN-induced urinary bladder tumors when given before the carcinogen. CONCLUSION: Green tea may inhibit tumor initiation in the bladder.

Animals↗