Effects of Sodium Nitrite and Catechol, 3-Methoxycatechol, or Butylated
Hydroxyanisole in Combination in a Rat Multiorgan CarcinogenesisModel1
Masai»Hirose,2 Hikaru Tanaka, Satoru Takahashi, Mitsuru Futakuchi, Shoji Fukushima,3 and Nobuyuki Ito
First Department of'Ptitlwlo$\, Na#o\a Cit\ University Medical School, I Ktiwasumi. Mi~uho-iiw, Mi~uho-ku. Nuxo\n 467, Japan
ABSTRACT
I tin is of simultaneous treatment with NaNO2 and butylated hydroxy-anisole. catechol. or 3-methoxycatechol were examined in a rat multiorgan
carcinogenesis model. Groups of 15 animals were given a single i.p. injection of KM)mg/kg of body weight diethylnitrosamine, 4 i.p. injections of 20mg/kg of body weight ¿V-methylnitrosourea, 4 s.c. injections of 40 mg/kg ofbody weight dimethylhydrazine, p.o. treatment with 0.05% ¿V-butyl-AM4-
hydroxybutyhnitrosamine in the drinking water for the first 2 weeks andp.o. treatment with 0.1% 2,2'-dihydroxy-di-n-propylnitrosamine in the
drinking water for the next 2 weeks of the initial 4-week initiation period.
Starting 3 days after the completion of these carcinogen treatments, animals were given diets containing 2% butylated hydroxyanisole. 0.8%catechol, 2% 3-melhoxycatechol, or basal diet either alone or in combi
nation with 0.3% sodium nitrite until week 28, when complete autopsy wasperformed.
Histológica! examination showed that NaNO2 strongly enhanced development of forestomach lesions but inhibited that of glandular stomachlesions in rats simultaneously given catechol or 3-methoxycatechol with orwithout prior carcinogen exposure. 3-Methoxycatechol promoted esoph-
ageal carcinogenesis either with or without N.iM ).. but promoting effectsof catechol were evident only in the presence of ViNOj. In addition,treatment with ViM >•¿�after carcinogen exposure enhanced forestomachcarcinogenesis. These results indicate that NaNO2 can modify phenolicantioxidant-induced cell proliferation and/or carcinogenesis. particularly
in the upper digestive tract.
INTRODUCTION
Recently the phenolic antioxidants BHA.4 caffeic acid, sesamol.
and catechol have been shown to be carcinogenic for rodent forestomach or glandular stomach epithelia ( l^J). Of these compounds. BHA.caffeic acid, and catechol all enhanced 2-stage rat stomach carcinogenesis initiated with MNNG (5-9), 7,12-dimethylbenz(if (anthracene
(10), DBN (II). or MNU (12, 13). However, the same group ofphenolic antioxidants is well known to be capable of inhibiting carcinogenesis by reducing active nitrosamine formation. For example,chlorogenic acid, caffeic acid, ferulic acid, gallic acid, and syringolhave been shown to block in vivo or in vitro formation of nitrosamines( 14-17) or inhibit in vivo tumor induction by NaNO2 and amines (16).On the other hand, the reaction of phenol with NaNO2 under mildlyacidic conditions produces p-nitrosophenol and diazoquinones, p-di-
azoquinone being demonstrated to possess mutagenicity in Salmonella typliimurim TA 98 and TA 100 without metabolic activation ( 18).
Received 6/29/92; accepted 10/19/92.The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section 1734 solely to indicate this fact.
1This work was supported by a Grant-in-Aid for Cancer Research from Ihe Ministryof Education. Science and Culture, a grunt from the Ministry of Health and Welfare, anda grant from the Society for Promotion of Pathology of Nagoya.
- To whom requests tor reprints should be addressed.1Present address: First Department of Pathology. Osaka City University Medical
School. 1-4-54. Asahi-machi. Abeno-ku. Osaka. 545. Japan.4 The abbreviations used are: BHA. butylaled hydroxyanisole: MNNG. /V-methyl-W-
Similarly, phenol. 3-methoxycatechol. and catechol all exhibit direct-acting genotoxicity as evaluated by the SOS Chromotest after nitro-
sation in acidic conditions, diazonium compounds being considered tobe responsible for the genotoxicity ( 19). In contrast, BHA was foundnot to be genotoxic in the presence of NaNO2 under acidic conditions(19). However, it was shown that a reaction mixture of BHA andnitrite in acidic condition produced t-BQ and the dimer of t-BQ which
are positive in the Ames and Ree mutation assays (20). It is conceivable that these diazonium compounds or quinone metabolites could beproduced in the rat stomach when NaNO2 and BHA. 3-methoxycat
echol. or catechol are administered in combination, and therefore it isof interest to examine whether such compounds have tumorigenicpotential for the gastric mucosa or other organs.
Recently we have developed several /';; vim multiorgan carcino
genesis models for the detection of carcinogens, promoters, or inhibitors in rats subjected to wide-spectrum initiation protocols. In these
animal models, it is possible to examine the effects of chemicals inmultiple organs in a single experiment (21-26). The present paper
concerns the effects of NaNO2 and the phenolic antioxidants catechol.3-methoxycatechol. or BHA. either in combination or alone in a rat
multiorgan carcinogenesis model.
MATERIALS AND METHODS
Eight groups of 6-week-old male F344 rats. 15/group (Charles River Japan
Inc.. Kanagawa. Japan) were treated with a single i.p. injection of 1(X)mg/kgof body weight of DEN. Starting 2 days after DEN treatment, they weresequentially given tour i.p. injections of 20 mg/kg of body weight of MNUfollowed by four s.c. injections of 40 mg/kg body weight of 1.2-dimethylhv-
dra/ine every 2 or 3 days. At the start of DEN injections, they were treated with0.05% BBN in the drinking water for 2 weeks, followed by 0.1% DHPN in thedrinking water for 2 more weeks. Experimental schedule was shown in Fig. 1.Starting 3 days after termination of the DHPN treatment, they were administered 0.3% NaNO2 in the drinking water, and/or 2% BHA (purity. >98%).0.8% catechol (purity. >98%). or 2% 3-methoxycatechol (purity, >98%) in
alone or in combination, or basal diet alone until the 28th week. An additional8 groups of 10 animals each were similarly treated with 2% BHA. 0.8%catechol. or 2% 3-methoxycatechol in diet either alone or in combination with
0.3% NaNO2 in the drinking water, or basal diet alone without the carcinogenpretreatments. NaNO2. catechol. and 3-methoxycatechol were purchased from
Wako Pure Chemical Industries. Osaka. Japan: DEN and BBN were fromTokyo Kasei Kogyo. Co.. Tokyo. Japan; MNU was from Iwai Kagaku Yakuhin.Co.. Tokyo: DHPN was from Nakarai Chemical Co.. Osaka: and 1,2-dimeth-
ylhydrazine was from Aldrich Chemical Co.. Inc.. Milwaukee. WI. BHA andcatechol were stable in diet as previously reported (2, 7).
Animals were kept 5 to a plastic cage in an air-conditioned room at 24 ±2°C,and food and water consumption were measured every 2—4weeks during
the chemical treatment test period. At week 28, all animals were killed underether anesthesia and were completely autopsied. Tissues were fixed in 10%buffered formalin solution and processed routinely for hematoxylin and eosinstaining. Forquantitive analysis of preneoplastic GST-P-positive foci, acetone-fixed liver sections were stained immunohistochemically with anti-GST-P an
tibody and foci were counted by using a color video image processor aspreviously reported (27). Only animals surviving until the end of the experiment were included in the calculations. The Fisher exact probability test andStudent's / test were used for the statistical analysis of the data.
Fig. I. Experimental design of the rat multiorgan carcinogenesis minie!. Animáis,maleF344 rats. 6 weeks old: I. DEN HX) mg/kg of body weight i.p.: V. MNU 20 ing/kg «Ibody weight i.p.; T. DMH 40 mg/kg of body weight •¿�,.<;.'Hi . BBN ().()5'/i in drinking
water; . DHPN O.F/f in drinking water;®?. lest chemicals. Groups I and 9. BHA(2% in dietl +NaNO; (0.37< in drinking water); Groups 2 and ID. BHA; Groups 3 andII. catechol (0.87r in diel) +NaNO.; Groups 4 and I2. eatechol; Groups 5 and I3.3-melhoxycalcchol (2r/f in diet) +NaNO,; Groups 6 and 14. 3-melhoxycalechol; Groups
7 and 15. NaNO_>;Groups 8 and 16. basal diel.
RESULTS
Final body weights, relative organ weights, and food consumptiondata are listed in Table 1. Final body weights for animals treated withantioxidants or NaNO> either with or without carcinogen pretreatment, were significantly lower than for those receiving basal dietalone. Combined treatment with antioxidants and NaNO, further reduced body weights as compared to antioxidant alone group values.On the other hand, relative liver and kidney weights in the combination treatment groups tended to be higher than in the individualtreatment groups. Food consumption was clearly lower in the combination groups.
Grossly, the most striking changes were observed in stomach epi-
thclki. Forestomach epithelia of rats treated with NaNO;. plus BHAturned yellowish and those treated with NaNO, plus catechol or3-methoxycatechol turned black with extensive mucosal thickeningcovered by a dense keratin-like substance.
Histopathological changes in the forestomach are presented inTables 2 and 3. Forestomach lesions were classified into hyperplasia,papilloma. carcinoma in situ, and squamous cell carcinoma: hyperplasia was further divided into mild, moderate, severe, and markedcategories, depending on the thickness of the mucosa as previouslyreported (9). In the groups given carcinogens, treatment with BHAsignificantly enhanced the incidence of papilloma, carcinoma in situ.
and squamous cell carcinoma, but additional treatment with NaNO;.did not modify these incidences. Catechol weakly (P < 0.05) enhanced the incidence of squamous cell carcinomas, and additionaltreatment with NaNO;. significantly enhanced the incidence of carcinoma in situ (P < 0.05) and squamous cell carcinomas (P < 0.00! ).3-Methoxycatechol significantly enhanced the induction of papillo-
mas (P < 0.01) and weakly enhanced that of carcinomas. Additionaltreatment with NaNO;. with 3-methoxycatechol did not further influ
ence the incidence of neoplastic lesions. Treatment of initiated animals with NaNO, alone significantly enhanced neoplastic lesion development. In the groups without carcinogen exposure, administrationof NaNOi remarkably enhanced the development of papillomasand/or hyperplasia induced by catechol or 3-methoxycatechol but not
by BHA. Treatment with NaNO, alone induced mild and moderatehyperplasia in 40 and 3()<7rof animals, respectively.
In the glandular stomach, lesions were classified into submucosalhyperplasia. adenoma, and adenocarcinoma categories as previouslyreported (28). In the carcinogen-treated groups, additional treatment
with NaNO, slightly inhibited the development of submucosal hyperplasia in rats given catechol. whereas the incidences of submucosalhyperplasia and adenomas were significantly reduced in those given3-methoxycatechol. In groups not receiving the initial carcinogens, all
rats treated with catechol had submucosal hyperplasia and adenomas,and 9 and 7 rats, respectively, treated with 3-methoxycatechol. had
submucosal hyperplasia and adenomas. The incidences of these lesions were remarkably reduced by the combined treatment withNaNO, (Table 4).
In the liver, numbers and/or areas of GST-P-positive foci were
reduced by the antioxidant treatments, the reduction being most apparent with the NaNO, plus 3-methoxycatechol group, but NaNO,
conversely inhibited the reduction caused by the BHA group (Table 5).In other organs examined (Table 6). NaNO, significantly reduced
the incidences of thyroid hyperplasia in BHA- and 3-methoxycate-chol-treated rats, and that of lung adenomas in BHA- and 3-methox-ycatechol-treated rats. 3-Methoxycatechol tended to enhance the de
velopment of tongue lesions with or without the presence of NaNO,.Incidences of esophageal papillomas were slightly higher with theadditional NaNO, treatment in the catechol and 3-methoxycatecholgroups, and 3-methoxycatechol alone significantly enhanced the in
duction of papillomas. In the kidney, catechol reduced the incidence ofnephroblastomas, and in the urinary bladder BHA enhanced that ofpapillomas.
Table I Final body ami ornan /IM. and avtragt footl coiiMunpiion iluia
"CIS, carcinoma in situ: SCC, squamous cell carcinoma.h P < 0.01 versus respective basal diet group values.(' P < 0.001 versus respective basal diet group values.
**P < 0.05 versus respective antioxidant alone group values.e P < 0.001 versus respective antioxidant alone group values.f P < 0.05 versus respective basal diet group values.
Table 3 Hisiopatholagical findings in forestomach of rats without carcinogen pretreatment
" P < 0.001 versus basal diet group values.b P < 0.05 versus respective antioxidant alone group values.1' P < 0.001 versus respective antioxidant alone group values.
**P < 0.05 versus basal diet group values.*"P < 0.01 versus basal diet group values.
Table 4 Histopathological findings in glandular stomach
" P < 0.05 versus respective antioxidant alone group values.h P < 0.001 versus respective basal diet group values.c P < 0.05 versus respective basal diet group values.äP < 0.001 versus respective anlioxidant alone group values.' P < 0.01 versus respective anlioxidant alone group values.f P < 0.01 versus respective basal diet group values.
11P < 0.01 versan respective antioxidant alone group values.'' P < 0.01 versus basul diet group values.1 P < 0.05 trrvM.v basal diet group values.tj P < 0.05 versus respective antioxidant alone group values.
Table 6 Oilier ii nl finding* in can-inoxen-ireuteti .(,»«'«/»'{incidence. c/c)
" CC, catechol: 3-MCC. 3-methylcatechol.'' P < 0.01 versus respective antioxidant alone group values.' P < 0.001 versus basal diet group values.
f< 0.01 versus basul diet group values.r P < 0.05 versus respective antioxidant alone group values.' P < 0.05 versus basal diet group values.
DISCUSSION
The present experiment showed that NaNO, can modify the influence of phenolic antioxidants on their target organs when given torats simultaneously with the antioxidants. This was dependent on theindividual antioxidant species. In the forestomach epithelium, BHAinduced hyperplasia and strongly enhanced forestomach carcino-
genesis, and additional treatment with NaNCK did not exert any effect.On the other hand. NaNO, clearly stimulated induction of hyperplasia
and enhanced forestomach carcinogenesis in catechol-treated animals.
The findings for antioxidants alone are in line with earlier studiesindicating that BHA and catechol strongly promote MNNG-, MNU-,or DBN-initiated rat forestomach carcinogenesis (6. 8. 9, 11, 13), with
the potency for induction of hyperplasia being well correlated withdegree of promotion (7, 9, 29, 30).
However, while 3-methoxycatechol induced forestomach hyper
plasia, and simultaneous treatment with NaNO, strongly stimulateddevelopment of hyperplasia. neither 3-methoxycatechol alone nor
3-methoxycatechol and NaNO2 in combinalion promoted forestomachcarcinogenesis. A similar dissociation between induction of hyper-
plasia and promotion of carcinogenesis has been observed tor thephenolic antioxidant 4-methoxyphenol. Thus p.o. treatment with 2c/c
4-methoxyphenol induced severe forestomach hyperplasia but did not
promote forestomach carcinogenesis initiated by MNNG in rats(7, 29). This was interpreted to mean that 4-methoxyphenol killsMNNG-initiated forestomach epithelial cells or that the type of in
duced hyperplasia (downward basal cell hyperplasia) lacks enhancinginfluence. In our own observations, combined treatment with 3-meth
oxycatechol and NaNO2 caused very strong forestomach epithelialdamage within 2 weeks, and 3-methoxycateehol-induced hyperplasia
was projected downward/ Therefore, the present lack of promotion inthe 3-methoxycatechol and NaNCK case is likely to be analogous tothat with 4-methoxyphenol.
Although NaNO2 was not found to be carcinogenic for rat fore-
stomach epithelium in an earlier study (31). it did induce significantincidence of forestomach hyperplasias and enhanced forestomach carcinogenesis in the present experiment, the indication being that itpossesses weak promotion activity.
In the glandular stomach epithelium. 3-methoxycatechol alone in
duced adenoma development, suggesting complete carcinogenic potential in the long term, as already discussed in a previous paper (32).In contrast to its influence in the forestomach. NaNO2 significantlyinhibited catechol- and 3-methoxycatechol-induced glandular stom
ach lesion development. This could have been partly due to suppression of food intake, but changes in metabolic pathways cannot beruled out. as discussed below. Only very weak promotion of glandularstomach carcinogenesis was apparent in rats treated with catechol inthe present experiment as compared to that observed previously afterMNNG initiation (7). This may be because the carcinogens appliedwere not appropriate for effective initiation of the glandular stomachepithelium.
With regard to the mechanism of how NaNO2 stimulates cell proliferation in the forestomach epithelium of rats treated with catecholand 3-methoxycatechol. it may be important that the mixture of cat
echol and NaNO2 under acidic conditions was found to producemutagenic diazonium compounds (19). In support of this, the '2P-
postlabeling method revealed a few spots on thin-layer chromatogra-
phy plates, indicating formation of DNA adducts. in the case offorestomach epithelium from rats treated with 0.8% catechol and 0.3%NaNO, in combination for 2 weeks, but not after treatment withcatechol alone (33). On the other hand, it might be possible that thereduced incidence of glandular stomach lesions in rats treated withcatechol or 3-methoxycatechol and NaNO, in combination is partly
due to reduced amounts of metabolites which target glandular stomachepithelium.
It is relevant that the combined treatment with NaNO2 did notinfluence the forestomach cell proliferation and promotion of carcinogenesis induced by BHA. It has been shown that genotoxic t-BQ is
formed in reaction mixtures of BHA and NaNO2 under acidic conditions (20). and t-BQ is one of the minor metabolites of BHA in theforestomach epithelium (34). This chemical exerts DNA-damagingactivity on rat forestomach epithelium in vivo (34). However t-BQ isalso known as a metabolite of rm-butylhydroquinone (35), which
lacks or has very little influence on forestomach cell proliferation (36.37). Taking into account these facts and the present results, it ispossible that t-BQ does not play an important role in BHA-induced
forestomach cell proliferation and carcinogenesis.In the other organs examined, NaNO2 reduced the incidence of lung
and/or thyroid neoplastic lesions in catechol- or 3-methoxycatechol-
"*Unpublished observation.
treated groups. These reductions might be largely due to reduction infood intake. Previously catechol and its isomers. hydroquinone andresorcinol, were demonstrated to promote esophageal and tongue carcinogenesis in rats initiated with /V-methyl-/V-amylnitrosamine (38),and catechol also exerted cocarcinogenic effects on /V-methyl-A'-amylnitrosamine-initiated rat esophageal carcinogenesis (39). In the
present experiment, although catechol only tended to enhance esophageal carcinogenesis. 3-methoxycatechol demonstrated significant
promotion potential. Furthermore, this promoting effect was stimulated by additional treatment with NaNO2. Therefore, it is stronglysuggested that 3-methoxycatechol is more effective than catechol in
enhancing esophageal carcinogenesis and that NaNO2 could be acopromoter in this system. In the urinary bladder epithelium. BHAenhanced urinary bladder carcinogenesis, as expected from earlierstudies (5), but this was not modulated by simultaneous treatment withNaNO2.
In conclusion, the present study demonstrated that NaNO2 canstimulate cell proliferation and enhance carcinogenesis when appliedwith certain phenolic antioxidants. particularly in the forestomachepithelium.
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