Stage and organ dependent effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone, ascorbic acid derivatives, N‐heptadecane‐8,10‐dione and phenylethyl isothiocyanate in a rat multiorgan carcinogenesis model

Ogawa, Kumiko; Futakuchi, Mitsuru; Hirose, Masao; Boonyaphiphat, Pleumjit; Mizoguchi, Yasumoto; Miki, Tsuyoshi; Shirai, Tomoyuki

doi:10.1002/(sici)1097-0215(19980610)76:6<851::aid-ijc14>3.3.co;2-2

Cited by 13 publications

(20 citation statements)

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“…The results are in line with our previous observations that 0.25% HTHQ weakly enhanced carcinogenesis in the tongue and forestomach, but not in the esophagus, in a rat medium term multi-organ model 30) and in an N-ethylnitrosourethane-initiated rat two-stage carcinogenesis model. 21) Furthermore, incidence of forestomach carcinomas was further increased by additional treatment with NaNO 2 .…”

Section: Discussionsupporting

confidence: 92%

Effects of Antioxidant 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone or Ascorbic Acid on Carcinogenesis Induced by Administration of Aminopyrine and Sodium Nitrite in a Rat Multi‐organ Carcinogenesis Model

Yada

Hirose

Tamano³

et al. 2002

Japanese Journal of Cancer Research

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The effect of antioxidant, 0.25% 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ) or 0.25% ascorbic acid (AsA), on carcinogenesis induced by administration of 0.05% aminopyrine (AP) and 0.05% sodium nitrite (NaNO 2 ), was examined using a rat multi-organ carcinogenesis model. Groups of twenty F344 male rats were treated sequentially with an initiation regimen of Ndiethylnitrosamine, N-methyl-N-nitrosourea, N-butyl-N-(4-hydroxybutyl)nitrosamine, N,N′ ′ ′ ′-dimethylhydrazine and 2,2′ ′ ′ ′-dihydroxy-di-n-propylnitrosamine during the first 4 weeks, followed by AP + + + +NaNO 2 , AP + + + +NaNO 2 + + + +HTHQ, AP + + + +NaNO 2 + + + +AsA, NaNO 2 + + + +HTHQ, NaNO 2 + + + +AsA, each of the individual chemicals alone or basal diet and tap water as a control. All surviving animals were killed at week 28, and major organs were examined histopathologically for development of preneoplastic and neoplastic lesions. In the AP + + + +NaNO 2 group, the incidences of hepatocelluar adenomas and hemangiosarcomas were 95% and 35%, respectively. When HTHQ or AsA was simultaneously administered, the incidences decreased to 58% and 11%, or to 80% and 15%, respectively. On the other hand, in the AP + + + +NaNO 2 group and the NaNO 2 -alone group, when HTHQ, but not AsA, was simultaneously administered, the incidence of carcinomas in the forestomach significantly increased. The results suggest that HTHQ can prevent tumor production induced by AP and NaNO 2 more effectively than AsA. On the other hand, an enhancing or possible carcinogenic effect of simultaneous administration of HTHQ and NaNO 2 only on the forestomach is suggested, while simultaneous treatment with the same dose of AsA and NaNO 2 may not be carcinogenic to the forestomach or other organs.Key words: Antioxidants -Aminopyrine -Sodium nitrite -Carcinogenesis -RatMany nitrosoamines are known to induce tumors in various organs.1) It was reported that some drugs with secondary or tertiary amino groups reacted with nitrite under acidic conditions to form nitrosamines in vitro and in vivo. [2][3][4][5] In particular, aminopyrine (AP) is known to react with sodium nitrite (NaNO 2 ) to form dimethylnitrosamine (DMN), which is a potent liver, lung and renal carcinogen.2, 3, 6) Feeding of AP and NaNO 2 to rats has been shown to cause acute liver damage due to formation of DMN and eventually to cause liver tumors upon chronic treatment. 2,7,8) It is also known that ascorbic acid (AsA), and phenolic antioxidants such as caffeic acid, ferulic acid, butylated hydroxyanisole (BHA) and propyl gallate, inhibit the formation of DMN in rats receiving AP and NaNO 2 . 4,5) An inhibitory effect of caffeic acid on the endogenous formation of N-nitrosoproline was demonstrated in man. 9)Kuenzig et al. suggest that dietary phenols may play an important role in the prevention of carcinogenesis by inhibiting the formation of nitrosamines. 5)On the other hand, it has been reported that mutagenic compounds were formed by the interaction of polyphenols with nitrite in vitro.10, 11) It was also reported tha...

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Section: Discussionsupporting

confidence: 92%

Effects of Antioxidant 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone or Ascorbic Acid on Carcinogenesis Induced by Administration of Aminopyrine and Sodium Nitrite in a Rat Multi‐organ Carcinogenesis Model

Yada

Hirose

Tamano³

et al. 2002

Japanese Journal of Cancer Research

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“…These oxidative phenomena may lead to necrotic cell death and thus damage to the surrounding cells. Although ITCs are promising and effective candidates as anticarcinogens, some ITCs showed enhancement of carcinogenicity or lack of chemopreventive effects in rat liver and kidney especially dosed at the post-initiation phase (52,53). It is very likely that the intracellular ROS generation plays an important role in unfavorable side effects of BITC on carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the Mitochondrial Death Pathway in Chemopreventive Benzyl Isothiocyanate-induced Apoptosis

Nakamura¹,

Kawakami²,

Yoshihiro³

et al. 2002

Journal of Biological Chemistry

159

150

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In the present study, we studied the molecular mechanism underlying cell death induced by a cancer chemoprotective compound benzyl isothiocyanate (BITC). The cytotoxic effect of BITC was examined in rat liver epithelial RL34 cells. Apoptosis was induced when the cells were treated with 20 M BITC, characterized by the appearance of phosphatidylserine on the outer surface of the plasma membrane and caspase-3 activation, whereas no caspase activation and propidium iodide incorporation into cell were detected with 50 M BITC that induced necrosis. The mitochondrial death pathway was suggested to be involved in BITC-induced apoptosis because the treatment of cells with BITC-induced caspase-9-dependent apoptosis and mitochondrial transmembrane potential (⌬⌿m) alteration. We demonstrated here for the first time that BITC directly modifies mitochondrial functions, including inhibition of respiration, mitochondrial swelling, and release of cytochrome c. Moreover, glutathione depletion by diethyl maleate significantly accelerated BITC-triggered apoptosis, suggesting the involvement of a redox-dependent mechanism. This was also implicated by the observations that intracellular accumulation of reactive oxygen species, including superoxide (O 2 . ) and hydroperoxides (HPOs), was indeed detected in the cells treated with BITC and that the intracellular HPO level was significantly attenuated by pretreatment with N-acetylcysteine. The treatment with a pharmacological scavenger of O 2 . , Tiron, also diminished the HPO formation by ϳ80%, suggesting that most of the HPOs were H 2 O 2 derived from the dismutation of O 2 . . These results suggest that BITC induces apoptosis through a mitochondial redox-sensitive mechanism.

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“…6) Another synthetic phenolic antioxidant, BHA, a known forestomach carcinogen, promotes development of forestomach squamous cell carcinomas in rats pretreated with N-methyl-N′-nitro-Nnitrosoguanidine (MNNG) when given at 1%, 9) whereas catechol at 0.8% and tert-butylhydroquinone (TBHQ) at 1% only affected papillomas in multi-organ 10,11) models. In line with the present study, the same dose of HTHQ also increased the incidence and numbers of tongue papillary or nodular (PN) hyperplasias (P<0.001), and forestomach PN hyperplasias (P<0.01) in rats after initiation with ENUR (unpublished results).…”

Section: Discussionmentioning

confidence: 99%

“…HTHQ has the highest anti-mutagenic activity against Glu-P-1-induced mutagenesis 2) and chemopreventive effect against MeIQx-induced hepatocarcinogenesis among HTHQ, BHA, BHT, TBHQ, propyl gallate and α-tocopherol (unpublished results). In addition HTHQ inhibits colon 6) and mammary carcinogenesis 5) when given in the post-initiation stage in multi-organ and DMBA models, respectively. Thus, HTHQ still deserves consideration as a candidate chemopreventive agent suitable for human use.…”

Section: Discussionmentioning

confidence: 99%

Dose Dependence of 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone Promotion of Forestomach Carcinogenesis in Rats Pretreated with N‐Ethylnitrosourethane

Mizoguchi

Hirose

Yamaguchi

et al. 1998

Japanese Journal of Cancer Research

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Post-initiation dose-dependent effects of the chemopreventive antioxidant 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), a potent inhibitor of heterocyclic amine-induced mutagenesis and carcinogenesis, on the development of forestomach and tongue tumors were investigated in male F344 rats. Groups of 22 rats were treated with 0.01% ethylnitrosourethane (ENUR) as an initiator in the drinking water for 4 weeks, then placed on diet containing 1.0%, 0.5%, 0.25% or 0.125% HTHQ, or basal diet alone for 36 weeks. Further groups of 12 rats each were similarly treated with the different doses of HTHQ or given basal diet alone for 36 weeks without prior ENUR treatment. All animals were killed at week 40. Tongue papillary hyperplasia and papillomas tended to be increased in the groups treated with ENUR followed by 0.5-0.125% HTHQ, though there was no effect at the highest dose, in line with increased bromodeoxyuridine labeling indices. In the forestomach, the incidences of papillomas and carcinomas were also significantly elevated only in the group treated with ENUR followed by 0.125% HTHQ. Without ENUR pretreatment, papillary hyperplasia was found in the 1-0.125% HTHQ groups and the labeling index was also increased, though without clear dose dependence. The results indicate that HTHQ may have very weak or weak promotion potential for tongue and forestomach carcinogenesis, but that both minimum and maximum thresholds for active dose levels may exist.

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Stage and organ dependent effects of 1‐O‐hexyl‐2,3,5‐trimethylhydroquinone, ascorbic acid derivatives, N‐heptadecane‐8,10‐dione and phenylethyl isothiocyanate in a rat multiorgan carcinogenesis model

Cited by 13 publications

References 1 publication

Effects of Antioxidant 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone or Ascorbic Acid on Carcinogenesis Induced by Administration of Aminopyrine and Sodium Nitrite in a Rat Multi‐organ Carcinogenesis Model

Effects of Antioxidant 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone or Ascorbic Acid on Carcinogenesis Induced by Administration of Aminopyrine and Sodium Nitrite in a Rat Multi‐organ Carcinogenesis Model

Involvement of the Mitochondrial Death Pathway in Chemopreventive Benzyl Isothiocyanate-induced Apoptosis

Dose Dependence of 1‐O‐Hexyl‐2,3,5‐trimethylhydroquinone Promotion of Forestomach Carcinogenesis in Rats Pretreated with N‐Ethylnitrosourethane

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