Enhancing effect of concomitant L-ascorbic acid administration on BHA-induced forestomach carcinogenesis in rats

The effects of the synthetic antioxidant butylated hydroxyanisole(BHA) and naturally occurring antioxidants such as L-ascorbicacid (AsA; vitamin C), citric acid, benzoic acid or gallic acidin combination, on the development of rat forestomach epitheliallesions were investigated. A dietary level of 2.0% was selectedfor all antioxidants and the experimental period was 1 year.As compared with BHA alone, treatment with AsA in combinationwith BHA increased the severity of the hyperplasia in the mid-region,but not the prefundic region of the forestomach epithelium,as well as the multiplicity of forestomach tumors. Furthermore,incidences of squamous cell carcinomas (SCCs) in the forestomachwere significantly elevated in this group, while papilloma developmentonly showed a tendency to increase. In addition, SCC invasioninto the muscle layer of the forestomach was observed only inthe BHA + AsA group. Treatment with the other antioxidants didnot affect BHA-induced forestomach lesion development. The presentstudy demonstarted that AsA can clearly enhance BHA forestomachcarcinogenesis.     

Different modifying response of butylated hydroxyanisole, butylated hydroxytoluene, and other antioxidants in N,N-dibutylnitrosamine esophagus and forestomach carcinogenesis of rats

The modifying effects of antioxidants were examined in a carcinogenesis system after N,N-dibutylnitrosamine treatment. Male F344 rats were given 0.05% N,N-dibutylnitrosamine in their drinking water for 4 wk and then treated with basal diet containing 2% butylated hydroxyanisole (BHA), 1% butylated hydroxytoluene (BHT) with 7 ppm vitamin K, 0.8% ethoxyquin, 5% sodium L-ascorbate, 5% sodium erythorbate, or no added chemical for 32 wk. BHA enhanced forestomach carcinogenesis but did not enhance esophageal carcinogenesis. BHT enhanced esophageal carcinogenesis but did not enhance forestomach carcinogenesis. Ethoxyquin significantly enhanced esophageal tumorigenesis. Neither esophageal nor forestomach carcinogenesis was affected by the other antioxidants evaluated. BHA significantly increased DNA synthesis of the forestomach epithelium, whereas BHT tended to increase that of the esophageal epithelium. Thus, BHA and BHT showed different modifying responses in carcinogenesis of the esophagus and forestomach.     

Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4- methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi- organ carcinogenesis model

The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4- hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n- propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.      

Histologic and autoradiographic studies on the forestomach of hamsters treated with 2-tert-butylated hydroxyanisole, 3-tert-butylated hydroxyanisole, crude butylated hydroxyanisole, or butylated hydroxytoluene

The inductions of hyperplasia and neoplastic lesions in the forestomach of Syrian golden hamsters by 2-tert-butylated hydroxyanisole [(2-tert-BHA) CAS: 121-00-6], 3-tert-butylated hydroxyanisole [(3-tert-BHA) CAS: 88-32-4], crude butylated hydroxyanisole [(BHA) CAS: 25013-16-5], and butylated hydroxytoluene [(BHT) CAS: 128-37-0] were compared histopathologically and autoradiographically. In hamsters fed the 2-tert-BHA diet, severe hyperplasia developed from week 4, reaching a maximum level in week 16 of 0.56 cm/10 cm basement membrane (bm), and papillomatous lesions appeared in week 16 (0.13 cm/10 cm bm). In hamsters fed 3-tert-BHA or crude BHA, severe hyperplasia developed from week 1, which reached a maximum level in week 4 of 3.63 cm/10 cm bm with 3-tert-BHA and 5.10 cm/10 with crude BHA; it then decreased. Papillomatous lesions were found in week 3 in hamsters fed 3-tert-BHA and in week 4 in hamsters fed crude BHA; they increased to maximum levels in week 16 of 0.50 cm/10 cm bm with 3-tert-BHA and 0.29 cm/10 cm bm with crude BHA. Mild hyperplasia occurred slightly more often in hamsters fed the BHT diet than in the control group. BHT induced no severe hyperplasia and papillomatous lesions. Changes in the labeling index of the forestomach epithelium paralleled the histologic changes, except in hamsters fed the BHT diet in which no significant increase in the labeling index was observed throughout the experiment. These data suggest that the tumorigenic action of crude BHA on hamster forestomach is largely due to 3-tert-BHA and that BHT does not induce forestomach tumors in hamsters.     

Combined effects of butylated hydroxyanisole and other antioxidants in induction of forestomach lesions in rats

The possibility that changes in the forestomach of rats induced by butylated hydroxyanisole (BHA) are caused by inductions of free radicals and their reactions with macromolecules was examined. Groups of five male F344 rats were pretreated with 1% alpha-tocopherol, 1% ellagic acid, 1% propyl gallate, 0.25% ethoxyquin, 0.5% glutathione, 1% sodium L-ascorbate or 1% 3,3'-thiodipropionic acid for 1 week, then treated with the same antioxidant plus 1% BHA for 1 week, and then killed. Histological examination showed that BHA induced epithelial hyperplasia of the forestomach. This induction of hyperplasia was not inhibited, but increased by the antioxidants, particularly propyl gallate and ethoxyquin. Thus the induction of hyperplasia by BHA may not be related to a free radical reaction.     

The Modifying Effects of Indomethacin or Ascorbic Acid on Cell Proliferation Induced by Different Types of Bladder Tumor Promoters in Rat Urinary Bladder and Forestomach Mucosal Epithelium

The effects of indomethacin (IM) or L-ascorbic acid (AsA) on cell proliferation induced by bladder tumor promoters such as butylated hydroxyanisole (BHA), sodium L-ascorbate (Na-AsA), sodium citrate (Na-Cit), and diphenyl (DP) in rat bladder and forestomach epithelium were investigated. Treatment with IM in combination with BHA or Na-AsA diminished DNA synthesis levels of bladder epithelium as compared to the BHA or Na-AsA alone values. On the other hand, AsA further amplified the increase of bladder epithelial DNA synthesis caused by Na-Cit treatment. Histopathologically, administration of Na-AsA in combination with IM reduced the incidence of simple hyperplasia. In contrast, simultaneous treatment with Na-Cit and AsA caused an increase of the hyperplasia development. No apparent combination effects were observed in the DP-treated groups. In forestomach epithelium, AsA enhanced the BHA-induced increase in DNA synthesis and epithelial hyperplasia, characterized by marked basal cell proliferation. The present results thus suggested that IM may exert inhibitory effects on promotion of bladder carcinogenesis by certain tumor promoter types, and AsA may enhance BHA forestomach carcinogenesis.     

The modifying effects of indomethacin or ascorbic acid on cell proliferation induced by different types of bladder tumor promoters in rat urinary bladder and forestomach mucosal epithelium.

The effects of indomethacin (IM) or L-ascorbic acid (AsA) on cell proliferation induced by bladder tumor promoters such as butylated hydroxyanisole (BHA), sodium L-ascorbate (Na-AsA), sodium citrate (Na-Cit), and diphenyl (DP) in rat bladder and forestomach epithelium were investigated. Treatment with IM in combination with BHA or Na-AsA diminished DNA synthesis levels of bladder epithelium as compared to the BHA or Na-AsA alone values. On the other hand, AsA further amplified the increase of bladder epithelial DNA synthesis caused by Na-Cit treatment. Histopathologically, administration of Na-AsA in combination with IM reduced the incidence of simple hyperplasia. In contrast, simultaneous treatment with Na-Cit and AsA caused an increase of the hyperplasia development. No apparent combination effects were observed in the DP-treated groups. In forestomach epithelium, AsA enhanced the BHA-induced increase in DNA synthesis and epithelial hyperplasia, characterized by marked basal cell proliferation. The present results thus suggested that IM may exert inhibitory effects on promotion of bladder carcinogenesis by certain tumor promoter types, and AsA may enhance BHA forestomach carcinogenesis.     

Modifying effects of concomitant treatment with butylated hydroxyanisole or butylated hydroxytoluene on N,N-dibutylnitrosamine-induced liver, forestomach and urinary bladder carcinogenesis in F344 male rats

The modifying effects of concomitant antioxidant treatment on N,N-dibutylnitrosamine (DBN)-induced carcinogenesis were investigated. Male F344 rats were given 0.05% DBN in their drinking water for 16 weeks, and simultaneously administered powder diet containing 2.0% butylated hydroxyanisole (BHA) or 0.7% butylated hydroxytoluene (BHT) for 16 weeks. Control animals received drinking water containing 0.05% DBN without antioxidant treatment. The final incidences of hepatocellular carcinomas were 100, 100 and 40% in the DBN plus BHA, DBN plus BHT and DBN treated groups, respectively, the difference being significant (P less than 0.001). Lung metastases were only observed in the DBN plus BHT group and DBN plus BHA group (50%, P less than 0.001; 7%, respectively). The incidence of papillary or nodular hyperplasia of the urinary bladder in the DBN plus BHA group was significantly higher than that of the control (P less than 0.05). Furthermore, esophageal carcinomas and papillomas were observed in all DBN treated groups, with no inter-group significant variation in yield. On the other hand, combination of DBN treatment with BHA or BHT significantly reduced the resultant incidences of forestomach hyperplasia. The results clearly demonstrated that concomitant administration of antioxidants, and in particular BHT, can modify DBN carcinogenesis.     

Enhancement of BHA-induced proliferative rat forestomach lesion development by simultaneous treatment with other antioxidants

Synergistic effects of butylated hydroxyanisole (BHA) and otherantioxidants on induction of rat forestomach lesions were investigated.Groups of F344 male rats were treated with 1% BHA phis 0.7%butylated hydroxytoluene (BHT), 1% BHA phis 1% propyl gallate(PG), 1% BHA plus 1% sodium L-ascorbate (SA), 1% BHA phis 1%DL--tocopherol (-TP), 0.4% BHT phis 0.4% BHA plus 0.4% PG plus0.4% SA plus 0.4% -TP, 1% BHA or 2% BHA. Further groups of 10rats each received antioxidants without BHA as controls. Histo-togfcalexamination revealed significantly increased incidences of hyperplasiain the groups given BHA together with SA or PG at the prefundicregion or at the mid region respectively. The forestomach changesinduced by BHA together with SA were equal to those inducedby 2% BHA. On the other hand, simultaneous treatment with BHAand PG or -TP reduced the incidence of hyperplasia at the prefundkregion. It is concluded that mixed treatment with BHA and otherantioxidants exerted enhancing or inhibitory effects on theinduction of hyperplasia at different sites of the forestomachepithelium.     

Effects of butylated hydroxyanisole, butylated hydroxytoluene, and NaCl on gastric carcinogenesis initiated with N-methyl-N'-nitro-N-nitrosoguanidine in F344 rats

Promoting activities of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and NaCl and of combinations of these antioxidants with NaCl on gastric carcinogenesis initiated by N-methyl-N'-nitro-N-nitrosoguanidine [(MNNG) (CAS: 70-25-7; 1-methyl-3-nitro-1-nitrosoguanidine] were investigated in male inbred F344 rats. Animals, 6-week old, were given an intragastric administration of MNNG at 150 mg/kg body weight by gastric tube and 1 week later were placed on a diet containing BHA (0.5%), BHT (1.0%), NaCl (5.0%), BHA (0.5%) plus NaCl (5%), or BHT (1.0%) plus NaCl (5.0%) for 51 weeks. Control rats received no further treatment after MNNG administration. A single intragastric application of MNNG to rats induced multiple epithelial tumors of the forestomach and a few epithelial tumors of the glandular stomach after 52 weeks. Squamous cell carcinomas of the forestomach were seen in 2 of 18 effective rats (11.1%) in the control groups, and the incidences in the groups receiving the subsequent treatment were 45.0% with BHA, 15.8% with BHT, 30% with NaCl, 70% with BHA plus NaCl, and 52.9% with BHT plus NaCl. Differences in the incidences of squamous cell carcinoma between the controls and groups given BHA, BHA plus NaCl, and BHT plus NaCl were statistically significant. NaCl given alone after MNNG administration also significantly increased the incidence of papillomas in the forestomach. Incidences of glandular stomach tumors, adenomas and carcinomas were not affected by any of the subsequent treatments. No tumors of the stomach developed in the groups given BHA, BHT, and NaCl without MNNG pretreatment. Thus the present experiment revealed that BHA and NaCl but not BHT exert promoting activity on MNNG-induced forestomach carcinogenesis in rats and that, when BHA and BHT were given with NaCl, promotion was more marked, suggesting a synergistic effect on tumor promotion.     

Co-carcinogenic Effect of Retinyl Acetate on Forestomach Carcinogenesis of Male F344 Rats Induced with Butylated Hydroxyanisole

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)-induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co-administration of 0.25% RA significantly (P<0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA-free water. In rats given 1% BHA, RA co-administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose-dependent enhancing effect on the development of the BHA-induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co-administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co-carcinogen in the BHA forestomach carcinogenesis of the rat.     

Co-carcinogenic effect of retinyl acetate on forestomach carcinogenesis of male F344 rats induced with butylated hydroxyanisole

The potential modifying effect of retinyl acetate (RA) on butylated hydroxyanisole (BHA)-induced rat forestomach tumorigenesis was examined. Male F344 rats, 5 weeks of age, were maintained on diet containing 1% or 2% BHA by weight and simultaneously on drinking water supplemented with RA at various concentrations (w/v) for 52 weeks. In groups given 2% BHA, although marked hyperplastic changes of the forestomach epithelium were observed in all animals, co-administration of 0.25% RA significantly (P less than 0.05) increased the incidence of forestomach tumors (squamous cell papilloma and carcinoma) to 60% (9/15, 2 rats with carcinoma) from 15% (3/20, one rat with carcinoma) in the group given RA-free water. In rats given 1% BHA, RA co-administered at a dose of 0.05, 0.1, 0.2 or 0.25% showed a dose-dependent enhancing effect on the development of the BHA-induced epithelial hyperplasia. Tumors, all papillomas, were induced in 3 rats (17%) with 0.25% RA and in one rat (10%) with 0.05% RA co-administration. RA alone did not induce hyperplastic changes in the forestomach. These findings indicate that RA acted as a co-carcinogen in the BHA forestomach carcinogenesis of the rat.     

Regression of simple hyperplasia and papillomas and persistence of basal cell hyperplasia in the forestomach of F344 rats treated with butylated hydroxyanisole

The reversibility of forestomach lesions induced in rats by butylated hydroxyanisole (BHA) was examined. F344 rats were given a 2% BHA diet for 24, 48, or 72 wk followed by a basal diet for the remainder of the 96-wk experiment. Two other groups of rats were given a 2% BHA diet or basal diet alone for 96 wk. The forestomach lesions at wk 24, 48, 72, or 96 were compared histopathologically. The results showed that exophytic epithelial proliferation (simple hyperplasia or papilloma) induced by BHA was reversible, while endophytic proliferation of basal cells (basal cell hyperplasia) persisted after withdrawal of BHA administration. This suggests that simple hyperplasia and papilloma of the forestomach induced by BHA are not autonomous and need continuous feeding of BHA to develop further.     

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.     

Inhibition of binding of 2-acetylaminofluorene to DNA by butylated hydroxytoluene and butylated hydroxyanisole in vitro

Numerous studies have shown that the food antioxidants butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA), under specific exposure conditions, can inhibit hepatocarcinogenesis induced by various carcinogens. The purpose of the present work was to study the biochemical mechanisms responsible for the anticarcinogenic activity of BHA and BHT using in vitro systems. The effects of BHA and BHT on the binding of 2-acetylaminofluorene (2-AAF) to DNA was determined in a microsomal system and in primary cultures of rat hepatocytes. It was found that both antioxidants reduce the binding of 2-AAF and that of N-OH-2-acetylaminofluorene (N-OH-2-AAF) to calf thymus DNA in the presence of liver microsomes. The inhibition was however more pronounced with the parent compound. Lower levels of DNA binding were also detected in hepatocytes incubated with 2-AAF along with BHA or BHT. These results suggest that phenolic antioxidants can exert anticarcinogenic activity through modulation of carcinogen interaction with DNA which may reflect on alteration in carcinogen metabolic activation.     

Stomach carcinogenicity of caffeic acid, sesamol and catechol in rats and mice

The carcinogenic potential of caffeic acid, sesamol and catechol was examined in male and female F344 rats and B6C3F1 mice, groups of 30 animals being treated with diets containing 2% caffeic acid, 2% sesamol or 0.8% catechol for 104 weeks (rats) or 96 weeks (mice). Histological examination revealed that caffeic acid induced forestomach squamous cell carcinoma in 57% (P less than 0.001 vs. controls) and 50% (P less than 0.001) of male and female rats, respectively, whereas sesamol was associated with squamous cell carcinoma at incidences of 31% (P less than 0.001) in male rats, and 38% (P less than 0.001) and 17% (P less than 0.05) in male and female mice, respectively. Catechol induced glandular stomach adenocarcinomas in 54% (P less than 0.001) and 43% (P less than 0.001) of male and female rats, respectively. The results thus clearly demonstrated that all three antioxidants are carcinogenic in rodent stomach epithelia.     

Stomach Carcinogenicity of Caffeic Acid, Sesamol and Catechol in Rats and Mice

The carcinogenic potential of caffeic acid, sesamol and catechol was examined in male and female F344 rats and B6C3F₁ mice, groups of 30 animals being treated with diets containing 2% caffeic acid, 2% sesamol or 0.8% catechol for 104 weeks (rats) or 96 weeks (mice). Histological examination revealed that caffeic acid induced forestomach squamous cell carcinoma in 57% ( P <0.001 vs. controls) and 50% ( P <0.001) of male and female rats, respectively, whereas sesamol was associated with squamous cell carcinoma at incidences of 31% ( P <0.001) in male rats, and 38% ( P <0.001) and 17% ( P <0.05) in male and female mice, respectively. Catechol induced glandular stomach adenocarcinomas in 54% ( P <0.001) and 43% ( P <0.001) of male and female rats, respectively. The results thus clearly demonstrated that all three antioxidants are carcinogenic in rodent stomach epithelia.     

Effects of four antioxidants on N-methyl-N'-nitro-N-nitrosoguanidine initiated gastric tumor development in rats

The effects of antioxidant administration during the post initiation phase of gastric tumor development were investigated in male Wistar rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Animals (20/group) were given MNNG in the drinking water (100 mg/l) for 8 weeks, and for the duration of this treatment were also fed on diet supplemented with 10% sodium chloride. Thereafter, they were divided into 6 groups and were maintained on diet containing either 2% butylated hydroxyanisole (BHA), 1% BHA, 1% butylated hydroxytoluene (BHT), 1% ethoxyquin (EQ) or 1% DL-alpha-tocopherol (alpha-TP) for 32 weeks. A carcinogen control group was fed the basal diet without antioxidant supplementation. The experiment was terminated 40 weeks after the beginning of administration of MNNG and development of gastroduodenal tumors was determined histopathologically. EQ significantly increased the incidence of tumors in the glandular stomach. No modification of tumor development in this region of the organ were observed with 2% BHA, 1% BHA, 1% BHT or 1% alpha-TP, although both 2% BHA and 1% BHA induced and/or promoted tumor development in the forestomach. In addition, nephrocalcinosis was identified only in the kidneys of rats given EQ after MNNG treatment.     

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

The effects of antioxidants given in the post initiation phaseof colon tumor development were investigated in male F344 ratstreated with 1 ,2-dimethylhydrazine (DMH). Animals (20/group)were given s.c. injections of DMH at a dose of 20 mg/kg oncea week for four consecutive weeks. One week after the last injection,rats were fed diet containing 5% sodium L-asorbate (SA), 0.5%butylated hydroxyanisole (BHA), 0.8% ethoxyquin (EQ), 1.0% propylgallate 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 injectionof DMH and all intestinal tumors were confirmed histologically.SA significantly increased the incidence of adenomas and thenumber of tumors per rat of the colon (especially of the distalcolon). Although EQ and BHT did not affect the number of ratswith colon tumors, the number of tumors per rat occurring inthe distal colon was significantly increased by EQ while beingdecreased by BHT. No modification of tumor development was observedwith BHA or PG. Thus, modification of tumor development by SA,EQ and BHT was apparent, mainly in the distal colon.     

Effect of antioxidants and antitoxicants of isoniazid on the formation of lung tumours in mice by isoniazid and hydrazine sulphate

The present study reports the effects of antioxidants and antitoxicants on the formation of lung tumours in Swiss mice induced by isoniazid (INH) and hydrazine sulphate (HS).Dietary administration of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or simultaneous oral administration of antitoxicants (l-arginine, l-sodium glutamate and pyridoxine hydrochloride) failed to prevent HS-induced lung tumours. On the other hand BHA and BHT inhibited the formation of lung tumours in groups of mice receiving INH. Folic acid supplementation had marginal effect on the formation of lung tumours in groups receiving HS (P < 0.1).Higher lung tumour incidence was observed in groups maintained only on BHT diet as compared to animals maintained on standard diet.