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PubMed1986

Effect of N-nitroso-n-butyl-(4-hydroxybutyl)amine exposure on the changes in mineral disposition caused by trisodium nitrilotriacetate.

Male Fischer 344 rats were used to determine effect of consumption of 0.5% N-nitroso-n-butyl-(4-hydroxybutyl)amine (BNN) in the drinking-water for 2 wk on the response to 0.02, 0.2 and 2.0% trisodium nitrilotriacetate (Na3 NTA . H2O) in the diet in terms of urinary mineral excretion, bladder mass and bladder mineral concentrations. The primary objective of the study was to determine whether exposure of rats to an initiating dose of a bladder carcinogen (BBN) alters the threshold dose of Na3NTA . H2O required to alter urinary or bladder mineral concentrations or the dose-response to NTA. Such alterations are considered to be necessary precursors for changes in bladder morphology in rats fed NTA in chronic toxicity studies (Anderson, Bishop & Campbell, CRC Crit. Rev. Toxicol. 1985, 15, 1). The results demonstrated that BBN exposure caused an increase in bladder mass and bladder-tissue Zn concentration. However, BBN pretreatment did not have any effect on Na3NTA . H2O metabolism, the threshold dose of Na3NTA . H2O required to attain the necessary conditions for induction of bladder toxicity by NTA, or the dose-response relationships for NTA's effects on any parameter examined. From these data, it is concluded that it is unlikely that NTA would show a different threshold or dose-response for bladder tumour promotion than for its tumorigenicity at this site, which has been demonstrated previously (National Cancer Institute, DHEW Publication No. (NIH) 77-806, 1977).

Acetates↗

PubMed1988

Effect of acute and chronic butylated hydroxyanisole administration on in vivo glucuronidation of N-nitrosobutyl(4-hydroxybutyl)amine in rats.

The urinary metabolic pattern of N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) administered ip at a dose of 5 mg/kg body weight was studied in animals either pretreated with butylated hydroxyanisole (BHA) as a single oral dose of 50 or 250 mg/kg, or fed a diet containing 0.1 or 0.5% BHA. The 24-hr urinary excretion of NB4HBA, its glucuronic acid-conjugate (NB4HBA-G) and N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA) in control rats were 0.12, 0.75 and 30% of the administered dose, respectively, and were not changed after a single oral dose of 50 mg BHA/kg. NB4HBA-G was significantly reduced in the urine of rats given 250 mg BHA/kg. In vitro assays carried out using rat-hepatic microsomal preparations as the source of the enzyme UDP-glucuronyl transferases (GT) and NB4HBA as the substrate, suggest that a competition between NB4HBA and BHA for the same enzyme may be the cause of the decreased NB4HBA-G excretion observed in vivo. A fourfold increase in NB4HBA-G urinary excretion was observed after chronic 0.5% BHA feeding; moreover, the glucuronic acid-conjugate of NB3CPA (NB3CPA-G), which was not detected in the controls or after acute BHA treatment, appeared in the urine of rats given dietary BHA for 3 wk, accounting for about 10% of the administered NB4HBA. In vitro experiments indicate that the increased glucuronides excretion may be the result of an elevated hepatic GT activity.

Animals↗

PubMed1991

Lack of bladder carcinogenicity of dietary sodium saccharin in analbuminaemic rats, which are highly susceptible to N-nitroso-n-butyl-(4-hydroxybutyl)amine.

A previous 1-wk study measuring the agglutinability of bladder epithelial cells by concanavalin A had suggested a high susceptibility of analbuminaemic rats to bladder carcinogenesis by sodium saccharin (Honma et al., Cancer Letters 1983, 19, 7). A long-term study was conducted to confirm the results of this short-term assay. Sodium saccharin was administered at 5% in the diet to groups of 35 male analbuminaemic rats and 36 male rats of the Sprague-Dawley strain. No bladder carcinomas nor precancerous lesions were observed in any of the rats exposed to sodium saccharin. The discrepancy between the results of the agglutination assay and the long-term experiment might be attributable to a sharp increase in urine volume in analbuminaemic rats during the first week of treatment. The resultant distension of the bladder wall might make the epithelial cells more susceptible to concanavalin A agglutination. The results indicated no demonstrable bladder carcinogenicity of sodium saccharin in analbuminaemic rats and excluded the possibility that these particular mutant rats could be useful animals for shorter-duration screening for bladder carcinogens.

Administration, Oral↗

PubMed1994

Modification of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in rats by phytic acid and its salts.

The effects of dietary phytic acid and its salts on the promotion stage of two-stage urinary bladder carcinogenesis were examined. Male F344 rats were initiated by exposure to 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk, and then treated with basal diet containing a 2% supplement of phytic acid (PA), phytic acid dodecasodium salt (Na-PA), phytic acid dodecapotassium salt (K-PA), phytic acid hexamagnesium salt n-hydrate (Mg-PA) or no added chemical for 32 wk. Na-PA significantly increased the development of preneoplastic and neoplastic lesions of the urinary bladder. K-PA also brought about a tendency for increase in papillomas, whereas Mg-PA and PA were without effect. Both Na-PA and K-PA caused elevation of urinary pH, and Na+ or K+ concentration, respectively. These results confirm the promoting activity of the sodium salt of phytic acid for urinary bladder carcinogenesis and indicate modulation by urinary components, as demonstrated by increases in urinary pH, and Na+ concentration.

Animals↗

PubMed1988

Effect of butylated hydroxyanisole added in vitro or administered to rats on N,N-dibutylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine metabolism by post-mitochondrial supernatant of liver homogenates.

The effect of butylated hydroxyanisole (BHA) on P-450-dependent omega-hydroxylation of N,N-dibutylnitrosamine (NDBA) to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and the further oxidation of BBN to N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN) by the alcohol/aldehyde dehydrogenase system was investigated using the post-mitochondrial supernatant of liver homogenates (S9) from acutely and chronically BHA pretreated animals or S9 fractions from untreated rats with BHA added. Acute oral BHA (50 and 250 mg.kg-1) did not change NDBA omega-oxidation, which was reduced by 35% only when the compound was administered 0.5% in the diet for 3 weeks. BCPN formation from BBN was unaffected by acute and chronic BHA pretreatment. In order to verify whether BHA or its metabolite(s) had a direct effect on NDBA and BBN oxidation, the compound was added to S9 fractions from untreated rats at various concentrations. Only when BHA concentrations were equimolar or in a 10-fold molar excess to the substrate concentration, we observed 30-50% inhibition of BBN formation and a reduced BCPN formation (60-80% of control values), from BBN. Thus, only at very high BHA concentrations could we confirm the inhibition of P-450-dependent mixed function oxidase and alcohol dehydrogenase activities involved in the metabolism of NDBA and BBN.

Administration, Oral↗

PubMedDate not supplied

Agglutination of isolated rat bladder cells by lectins after administration of N-butyl-N-(4-hydroxybutyl) nitrosamine.

Lectins, concanavalin A (Con A), wheat germ agglutinin (WGA), and Ricinus communis agglutinin (RCA) were used for agglutination of isolated rat bladder cells after administration of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). The results showed that WGA and RCA, as well as Con A, agglutinated rat bladder cells during the early stage of bladder carcinogenesis. The agglutinations by the 3 kinds of lectins were different; WGA and Con a agglutinated only BBN-treated cells but RCA agglutinated both BBN-membrane alterations during the early phase of bladder carcinogenesis.

Agglutination↗

PubMed1983

Effect of quercetin on two-stage carcinogenesis of the rat urinary bladder.

The initiating and promoting effects of quercetin on urinary bladder carcinogenesis in male F344 rats were examined histopathologically. No tumor or hyperplasia were observed in rats given 5.0% quercetin as initiator in the diet for 4 weeks followed by 0.001% N-butyl-N-(4-hydroxybutyl) nitrosamine (BHBN) for 29 weeks. Moreover, administration of 5.0% quercetin diet for 25 weeks after initiation with 0.01% BHBN for 4 weeks did not promote urinary bladder carcinogenesis. Furthermore, no lesions were detected in rats given 5.0% quercetin diet only. These results suggest that quercetin is not carcinogenic to rat urinary bladder.

Animals↗

PubMed1983

Agglutination assay of bladder cells by Concanavalin A proved the high susceptibility of analbuminemic rats to bladder carcinogens.

The susceptibility of analbuminemic rats, a mutant strain of Sprague-Dawley rats, to bladder carcinogens was examined by testing the agglutinability of isolated bladder epithelial cells by Concanavalin A (Con A). One-week treatment with 0.001% N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN) in the drinking water or 0.01% N-(4-(5-nitro-2-furyl)-2-thiazolyl)-formamide (FANFT), 0.01% and 0.1% 4-aminobiphenyl, 0.1% 4-nitrobiphenyl, 0.1% benzidine, 0.1% 2-napthylamine or 5% sodium saccharin in the diet clearly induced high agglutinability of bladder cells of male analbuminemic rats but not Sprague-Dawley rats. These results suggest that male analbuminemic rats are very susceptible to bladder carcinogens in general and therefore will be very useful in screening tests for bladder carcinogens.

2-Naphthylamine↗

PubMed1984

Delay of bladder cancer induction in rats treated with N-nitroso-N-butyl-N-(4-hydroxybutyl)amine by administration of sodium-2-mercaptoethanesulfonate (Mesna).

The influence of sodium-2-mercaptoethanesulphonate (Mesna) on urinary bladder cancer induced by N-nitroso-N-butyl-N-(4-hydroxybutyl)amine (BBNOH) was studied in male Sprague-Dawley rats. The treatment consisted of 5 g/kg BBNOH per gavage and 63 g/kg Mesna in drinking water over a period of 39 weeks. A positive control group was given the same dose of BBNOH as the treated group. Although Mesna did not reduce the incidence of bladder carcinomas, it significantly increased the lifespan of the animals, thus suggesting a partial general protective action.

Animals↗

PubMed1984

Promotion by ascorbic acid, sodium erythorbate and ethoxyquin of neoplastic lesions in rats initiated with N-butyl-N-(4-hydroxybutyl) nitrosamine.

The promoting effects of ascorbic acid, sodium erythorbate and ethoxyquin on two-stage urinary bladder carcinogenesis in F344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at a dose of 0.05% in the drinking water were examined. Administration of 5% sodium erythorbate in the diet significantly increased the incidences of preneoplastic lesions, papilloma and cancer of the urinary bladder, whereas administration of 5% ascorbic acid in the diet did not. Administration of 0.8% ethoxyquin also increased the incidence of neoplastic lesions. Administrations of 5% sodium L-ascorbate and 5% sodium erythorbate caused increases in the pH, the sodium content and crystals of MgNH4PO4 in the urine. These results show that sodium erythorbate and ethoxyquin promote urinary bladder carcinogenesis, while ascorbic acid does not.

Animals↗

PubMed1984

Promoting effects of unilateral ureteric ligation on two-stage urinary bladder carcinogenesis in rats.

The effect of ligation of the left ureter on the development of lesions in the urinary bladder were investigated in male F344 rats treated with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for 2 weeks followed by 0.002% N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) for 10 or 22 weeks. The lesions of the urinary bladder found in weeks 12 and 24 in rats treated with BBN and EHBN were preneoplastic papillary or nodular hyperplasia (PN hyperplasia), papilloma and cancer. The incidences and numbers of these lesions per 10 cm of basement membrane of urinary bladder were increased significantly by ureteric ligation. Treatment with BBN or EHBN only induced no remarkable change and thus the doses used were subcarcinogenic in the conditions used. The results show that unilateral ureteric ligation enhanced two-stage bladder carcinogenesis.

Animals↗

PubMed1985

Gamma glutamyl transpeptidase activity in rat urothelium treated with bladder carcinogens.

Gamma glutamyl transpeptidase (GGT) activity during urothelial carcinogenesis was examined histochemically in rats treated with N-methyl-N-nitrosourea (MNU) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN). GGT-positive cells developed with a high frequency in foci of nodulopapillary hyperplasia and carcinoma. GGT-positive cells, both individually and in nests, were also frequent in foci of simple hyperplasia and interlesion normal urothelium of carcinogen-treated bladders. The results suggest that development of GGT-positive cells in interlesion normal urothelium is specific to carcinogen treatment.

Animals↗

PubMed1986

Promoting effects of various agents in rat urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effects of various chemicals on the development of neoplastic lesions in the urinary bladder were investigated in male F344 rats given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as an initiator in their drinking water for 4 weeks. The compounds tested, indomethacin, acemetacin, epsilon-aminocaproic acid (EACA), diphenyl, allopurinol and acetaminophen (AAP), were added to the diet or drinking water for 32 weeks, and all animals were killed at the end of week 36. Of the chemicals tested, only diphenyl significantly increased the incidences and average numbers (per 10 cm basement membrane) of papillary or nodular hyperplasias (PN hyperplasia), papillomas and carcinomas of the urinary bladder over those in animals treated with BBN alone. These findings show that diphenyl is a promoter of urinary bladder carcinogenesis in male F344 rats.

Acetaminophen↗

PubMed1986

Delayed development of bladder cancer in male SD rats induced with N-nitroso-N-butyl-N-(4-hydroxybutyl)amine following concomitant administration of sodium 2-mercaptoethane sulfonate.

This study describes the prolonged survival of male SD-rats that bear bladder carcinomas induced either with 44 mg/kg or 28 mg/kg of N-nitroso-N-butyl-N-(4-hydroxybutyl)amine (BBNOH), when daily doses of 350 mg/kg of sodium-2-mercaptoethane sulfonate (mesna) were administered concomitantly. The difference to carcinogen-treated positive controls was highly significant (P = 0.0009 and 0.0013, respectively). Tumor volumes at time of death (P less than 0.005) and frequency of metastases were also reduced in rats that received both compounds in comparison to BBNOH-treated animals.

Animals↗

PubMed1987

Modification by alpha-tocopherol, propyl gallate and tertiary butylhydroquinone of urinary bladder carcinogenesis in Fischer 344 rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The promoting activity of 3 antioxidants, alpha-tocopherol (alpha-TP), propyl gallate (PG) and tertiary butylhydroquinone (TBHQ) in urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male F344 rats was examined. Rats, 6-week-old, were treated with 0.05% BBN in the drinking water for 4 weeks and then administered 1.50, 0.75 or 0.38% alpha-TP, 1.0% PG or 2.0% TBHQ in the diet for 32 weeks. The urinary bladder of all animals was examined histologically after the total 36 experimental weeks. The incidence of papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder was significantly higher in the rats treated with BBN followed by 2.0% dietary TBHQ that in controls initiated with 0.05% BBN followed by control diet. This result indicates that TBHQ has weak promoting activity in urinary bladder carcinogenesis. alpha-TP and PG did not demonstrate a promoting effect for urinary bladder lesions.

Animals↗

PubMed1987

Dose-dependent effects of butylated hydroxyanisole, butylated hydroxytoluene and ethoxyquin for promotion of bladder carcinogenesis in N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated, unilaterally ureter-ligated rats.

Dose-dependent effects of 3 antioxidants, butylated hydroxyanisole (BHA, 2.0, 1.0 and 0.5%), butylated hydroxytoluene (BHT, 1, 0.5 and 0.25%) and ethoxyquin (0.5, 0.25 and 0.125%) on the development of preneoplastic lesions in the bladder of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-treated rats were investigated. Feeding of the antioxidants after pretreatment of 0.05% BBN commenced and unilateral ureteric ligation was combined at week 3 of the experiment. Surviving rats were killed at the end of week 24. BHA and BHT, but not ethoxyquin increased dose-dependently the incidence and number of preneoplastic lesions, papillary or nodular hyperplasia of the urinary bladder in rats treated with BBN. Particularly, the incidence and number of PN hyperplasia in rats treated with 2.0% BHA and 1.0% BHT were significantly higher than those of the control group. Thus, promoting activities of BHA and BHT, but not ethoxyquin for the urinary bladder were confirmed in this system of BBN-initiated, unilaterally ureter-ligated rats.

Animals↗

PubMed1988

Assessment of L-ascorbic acid requirement for prolonged survival in ODS rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Assessment of L-ascorbic acid requirement for prolonged survival in ODS (genotype: od/od) rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were examined. In ODS rats without L-ascorbic acid synthesizing ability, the 50 ppm dietary total ascorbic acid (TAA) was insufficient to survive for 4 weeks, the 250 ppm dietary TAA was sufficient to survive for 36 weeks. In examination of BBN treatment, ODS rats--although showing a lower availability of TAA than the heterozygotes (+/od) and normal (+/+) rats with L-ascorbic acid synthesizing ability--were equally susceptible to bladder carcinogenesis.

Animals↗

PubMed1988

Combined effects of L-ascorbic acid, citric acid or their sodium salts on tumor induction by N-butyl-N-(4-hydroxybutyl)nitrosamine or N-ethyl-N-(4-hydroxybutyl)nitrosamine in the rat urinary bladder.

L-Ascorbic acid, citric acid or their sodium salts (at levels equivalent to 5% sodium L-ascorbate) were fed in the diet simultaneously with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) (0.025% BBN or 0.021% EHBN) in the drinking water to male F344 rats for 20 weeks to determine whether urinary pH changes affect the carcinogenicity of BBN or EHBN. In the urine, pH was decreased in rats fed the acidic chemicals and increased in rats fed their corresponding sodium salts. Histopathologically, the incidences and numbers of preneoplastic and neoplastic lesions in groups treated with each test chemical were not different from those in control groups except for sodium citrate-treated groups in which induction of carcinomas was higher, resulting from increased intake of either carcinogen and also from increased urinary excretion of main carcinogenic metabolites. These results show that the test chemicals do not affect the carcinogenicity of BBN or EHBN on the rat urinary bladder when simultaneously administered despite significant differences in urinary pH.

Animals↗