Different Responses Other than the Formation of DNA‐adducts between the Livers of Carcinogen‐resistant Rats (DRH) and Carcinogen‐sensitive Rats (Donryu) to 3′‐Methyl‐4‐dimethylaminoazobenzene Administration

Yan, Ying; Higashi, Ken; Yamamura, Kaori; Fukamachi, Yukiyo; Abe, Tetsuya; Gotoh, Sadao; Sugiura, Teiichi; Hirano, Takeshi; Higashi, Taneaki; Ichiba, Masayoshi

doi:10.1111/j.1349-7006.1998.tb00632.x

Cited by 17 publications

(20 citation statements)

References 38 publications

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“…Because DAB metabolism through the mono-oxygenase system is responsible for liver damage, decrease in P450 could ameliorate or delay this process (Yan et al, 1998). However, the significant increase in GST activity provoked by DAB still persisted in animals also receiving CIM, indicating that reduction in P450 by CIM is not enough to completely overcome DAB toxicity and suggesting that other mechanisms would be participating in the whole process.…”

Section: Discussionmentioning

confidence: 99%

Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

et al. 2002

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Many drugs and xenobiotics are lipophilic and they should be transformed into more polar water soluble compounds to be excreted. Cimetidine inhibits cytochrome P450. The aim of this study was to investigate the preventive and/or reversal action of cimetidine on cytochrome P450 induction and other metabolic alterations provoked by the carcinogen pdimethylaminoazobenzene. A group of male CF1 mice received a standard laboratory diet and another group was placed on dietary p-dimethylaminoazobenzene (0.5% w w 71 ). After 40 days of treatment, animals of both groups received pdimethylaminoazobenzene and two weekly doses of cimetidine (120 mg kg 71 , i.p.) during a following period of 35 days. Cimetidine prevented and reversed d-aminolevulinate synthetase induction and cytochrome P450 enhancement provoked by p-dimethylaminoazobenzene. However, cimetidine did not restore haem oxygenase activity decreased by p-dimethylaminoazobenzene. Enhancement in glutathione S-transferase activity provoked by p-dimethylaminoazobenzene, persisted in those animals then treated with cimetidine. This drug did not modify either increased lipid peroxidation or diminution of the natural antioxidant defence system (inferred by catalase activity) induced by p-dimethylaminoazobenzene. In conclusion, although cimetidine treatment partially prevented and reversed cytochrome P450 induction, and alteration on haem metabolism provoked by p-dimethylaminoazobenzene AB, it did not reverse liver damage or lipid peroxidation. These results further support our hypothesis on the necessary existence of a multiple biochemical pathway disturbance for the onset of hepatocarcinogenesis initiation.

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Section: Discussionmentioning

confidence: 99%

Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

et al. 2002

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“…These results support our previous finding that DNA damage other than bulky DNA adduct formation is involved in the carcinogenic mechanism of 3′-MeDAB. 8) To obtain further information about the repair capacity, we analyzed the mRNA level of the repair enzyme OGG1 by RT-PCR. The OGG1 protein is an 8-OH-Gua repair enzyme, and has glycosylase/lyase activities.…”

Section: Discussionmentioning

confidence: 99%

“…8) We concluded that DNA damage other than bulky DNA adduct formation was involved in the mechanism of 3′-MeDAB-induced carcinogenesis. We also suggested that the generation of reactive oxygen species occurred as well, because we observed a significant induction of cytochrome P-450 2E1 mRNA (CYP2E1) in the Donryu rat liver as compared to the DRH rat liver.…”

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confidence: 99%

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Analyses of Oxidative DNA Damage and Its Repair Activity in the Livers of 3′‐Methyl‐4‐dimethylaminoazobenzene‐treated Rodents

Hirano

Higashi

Sakai

et al. 2000

Japanese Journal of Cancer Research

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We measured the levels of 8‐hydroxyguanine (8‐OH‐Gua) and its repair activity in the livers of the Donryu rat, the carcinogen‐resistant DRH rat, and the ddy mouse, which were fed a 0.06% 3′‐ methyl‐4‐dimethylaminoazobenzene (3′‐MeDAB)‐containing diet. In a short‐term rat experiment (maximum 2 months), 3′‐MeDAB did not increase the 8‐OH‐Gua levels in the livers of the two rat strains, although it significantly increased the repair activity in only the Donryu rat liver at 1 and 2 months. After long‐term 3′‐MeDAB administration to the ddy mouse (8 months), the levels of 8‐OH‐Gua and its repair activity were increased in the liver by 3.6‐fold and 1.6‐fold, respectively. These experiments suggest that 3′‐MeDAB increases 8‐OH‐Gua generation in rodent liver DNA and the 8‐OH‐Gua repair assay is a reliable marker of cellular oxidative stress induced by carcinogens.

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“…Confusing tumors, especially small tumor nodules, were confirmed by histological examination of slices. in the livers of DRH/Sea and its parental Crj:Donryu rats [9]. Furthermore, comparable numbers of putatively preneoplastic glutathione S-transferase placental form (GST-P)-positive foci were detected after the SoltFarber protocol [7], but the area occupied by GST-P-positive lesions in the liver was much greater in Crj:Donryu rats than in DRH/Sea rats [3].…”

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Blunt Cell Growth Potential in Carcinogen Resistant Inbred DRH Rats.

et al. 2000

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A carcinogen-resistant inbred strain DRH/Sea has been developed from the Crj:Donryu strain. The rats had a very low incidence of liver tumors when they were fed diets containing a hepatocarcinogen such as 3'-methyl-4-dimethylamino-azobenzene (3'-Me-DAB). Despite using 3'-Me-DAB during the stage of selection, the DRH/Sea rats developed normally, reproduced and did not have any spontaneous tumor in the lung, liver or uterus at over 1 year of age. Although their growth curves were similar to the Crj:Donryu rats, the progression of polyploidization in the liver was significantly delayed when compared with Crj:Donryu rats. Mitogenic changes that occurred in the liver caused by either 3'-Me-DAB or lead nitrate were less significant in the DRH rats than in Crj:Donryu rats. Furthermore, the growth rate of cultured fibroblasts derived from the DRH rats was slower than that of Crj:Donryu rats. These results, together with our previous results, suggest that slow growth potential is present under certain conditions in DRH rats. These findings may explain partly the meaning of the different susceptibility to hepatocarcinogens. Key words: carcinogen-resistant rat, DRH/Sea, growth potential, ploidy but also in the uterus and via the milk. A pair of 12-week-old rats from the same litter were inbred and the rests were employed occasionally for the examination of either GGT-induction or hepatocarcinogenesis caused by 3'-Me-DAB. Therefore, many groups for inbreeding were maintained simultaneously, that is, more than 40 family lines on occasions. During this process, litters of rats that were premature at birth or grew poorly (Received 5 April 1999 / Accepted 8 July 1999 Corresponding address: K. Higashi, Department of Biochemistry, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Japan Carcinogen-resistant rats were first isolated from Crj:Donryu rats (Charles River Japan, Inc.) based on examination of selective markers such as reduced induction of γ-glutamyltranspeptidase (GGT) and a very low incidence of liver tumors due to 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) [10,11]. Briefly, all the rats were exposed continuously to 3'-Me-DAB and its metabolites not only after weaning

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Different Responses Other than the Formation of DNA‐adducts between the Livers of Carcinogen‐resistant Rats (DRH) and Carcinogen‐sensitive Rats (Donryu) to 3′‐Methyl‐4‐dimethylaminoazobenzene Administration

Cited by 17 publications

References 38 publications

Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

Analyses of Oxidative DNA Damage and Its Repair Activity in the Livers of 3′‐Methyl‐4‐dimethylaminoazobenzene‐treated Rodents

Blunt Cell Growth Potential in Carcinogen Resistant Inbred DRH Rats.

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