In vitro formation of organ-specific ultimate carcinogens of 4-dimethylaminoazobenzene and urethan by microsomes

Gupta, Raveena; Dani, H. M.

doi:10.1016/0378-4274(89)90158-6

Cited by 18 publications

(6 citation statements)

References 2 publications

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“…13,14) Restriction enzymes (SmaI, EcoRI, HindIII, ApaI, StyI and XbaI) and T 4 polynucleotide kinase were purchased from New England 3 To whom requests for reprints should be addressed. 16) A DNA fragment was prepared from plasmid pbcNI, which carries a 6.6-kb BamHI chromosomal DNA segment containing the human c-Ha-ras-1 protooncogene.…”

Section: Methodsmentioning

confidence: 99%

“…MAB is metabolized to 4-aminoazobenzene (AAB) through demethylation or to N-hydroxy-N-methyl-4-aminoazobenzene (N-OH-MAB) through N-hydroxylation, followed by further transformation to N-hydroxy-4-aminoazobenzene (N-OH-AAB). [3][4][5] N-Hydroxylation is believed to be a step leading aminoazo dyes to proximate carcinogenic or mutagenic metabolites. Watanabe and Hashimoto reported that N-OH-AAB elicited higher levels of unscheduled DNA synthesis (UDS) than AAB, suggesting higher DNA damaging activity of the N-hydroxy derivative than that of the corresponding mother aminoazo dye.…”

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confidence: 99%

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Oxidative DNA Damage Induced by an N‐Hydroxy Metabolite of Carcinogenic 4‐Dimethylaminoazobenzene

Ohnishi

Murata

Degawa

et al. 2001

Japanese Journal of Cancer Research

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Formation of adducts has been considered to be a major causal factor of DNA damage by carcinogenic aminoazo dyes. We investigated whether a metabolite of hepatocarcinogenic 4-dimethylaminoazobenzene (DAB) can cause oxidative DNA damage or not, using There is ample evidence for the carcinogenicity of 4-dimethylaminoazobenzene (DAB) in experimental animals. DAB induced lung tumors and hepatomas in mice and liver tumors in rats. In dogs it produced bladder tumors following oral administration. DAB has also been tested by s.c. injection in mice, and the results are suggestive of local and hepatic carcinogenicity.1) The International Agency for Research on Cancer (IARC) has assessed that DAB is possibly carcinogenic to humans (group 2B). 2)DAB is metabolized to N-methyl-4-aminoazobenzene (MAB) through N-demethylation. MAB is metabolized to 4-aminoazobenzene (AAB) through demethylation or to N-hydroxy-N-methyl-4-aminoazobenzene (N-OH-MAB) through N-hydroxylation, followed by further transformation to N-hydroxy-4-aminoazobenzene (N-OH-AAB). 3-5)N-Hydroxylation is believed to be a step leading aminoazo dyes to proximate carcinogenic or mutagenic metabolites. Watanabe and Hashimoto reported that N-OH-AAB elicited higher levels of unscheduled DNA synthesis (UDS) than AAB, suggesting higher DNA damaging activity of the N-hydroxy derivative than that of the corresponding mother aminoazo dye.6) It was also reported that N-OH-AAB dyes showed greater mutagenicity than the mother AAB dyes, without S-9 treatment.7) It is generally accepted that covalent binding of these metabolites with DNA is a major carcinogenic factor. 8) N-(Deoxyguanosin-8-yl)-4-aminoazobenzene was also obtained from mice or rats given an i.p. dose of AAB.4) It was regarded as an adduct formed by reaction of deoxyguanosine with a metabolite of AAB after N-hydroxylation and esterification. 4)On the other hand, N-OH-AAB and N-OH-MAB are reported to generate H 2 O 2 and O . 9) Administration of 3′-methyl-4-dimethylaminoazobenzene (3′-MeDAB) which is a stronger carcinogenic derivative of DAB, increased the levels of 8-hydroxyguanine and its repair activity in rodent liver DNA.10) These reports suggested that oxidative DNA damage plays a part in carcinogenesis by aminoazo dyes.To clarify the mechanism of carcinogenesis by DAB, we examined oxidative DNA damage induced by N-OH-AAB, using 32 P-5′-end-labeled DNA fragments obtained from the c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. In addition, we measured the content of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) in calf thymus DNA by high-performance liquid chromatography with an electrochemical detector (HPLC-ECD). It has been reported that 8-oxodG is a marker of oxidative DNA damage and that its formation can lead to DNA misreplication, resulting in mutation and cancer.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Oxidative DNA Damage Induced by an N‐Hydroxy Metabolite of Carcinogenic 4‐Dimethylaminoazobenzene

Ohnishi

Murata

Degawa

et al. 2001

Japanese Journal of Cancer Research

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“…It has been suggested that two compounds, vinyl carbamate and its epoxy derivative, may be the proximate and ultimate electrophilic metabolites responsible for genotoxicity and carcinogenicity of urethane, also known as ethyl carbamate. Epoxyethyl carbamate interacts with DNA to form 7-(2-oxoethyl)guanine adducts (28)(29)(30). Dimethylhydrazine is an alkylating agent and causes methylation of DNA generating O 6 -methylguanine (31,32), which has been shown to induce GC!AT transition mutations in the absence of DNA repair (33).…”

Section: Tep1mentioning

confidence: 99%

Increased Susceptibility of Vault Poly(ADP-Ribose) Polymerase–Deficient Mice to Carcinogen-Induced Tumorigenesis

Raval-Fernandes¹,

Kickhoefer²,

Ramirez

et al. 2005

Cancer Research

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Vault poly(ADP-ribose) polymerase (VPARP) and telomeraseassociated protein 1 (TEP1) are components of the vault ribonucleoprotein complex. Vaults have been implicated in multidrug resistance of human tumors and are thought to be involved in macromolecular assembly and/or transport. Previous studies showed that VPARP-deficient mice were viable, fertile, and did not display any vault-related or telomerase-related phenotype, whereas disruption of telomerase-associated protein 1 in mice led to reduced stability of the vault RNA and affected its stable association with vaults, although there were no telomerase-related changes. In this study, we evaluated the susceptibility of Vparp À/À and Tep1mice to dimethylhydrazine-induced colon tumorigenesis and urethane-induced lung tumorigenesis. Mice received i.p. injections of either 1 g/kg body weight of urethane twice a week for 2 weeks or 20 mg/kg body weight of dimethylhydrazine once a week for 10 weeks and were analyzed after 10 and 60 weeks, respectively. The colon tumor incidence and multiplicity were significantly higher and colon tumor latency was significantly shorter in Vparp À/À mice compared with wild-type mice. Increased colon tumor incidence, multiplicity, and reduced tumor latency were also seen in Tep1 À/À mice, however, these results were statistically not significant. Lung tumor multiplicities were increased in both Vparpand Tep1 À/À mice but were not significant. The increase in carcinogen-induced tumors in VPARP-deficient mice is the only phenotype observed to date, and suggests a possible role for VPARP, directly or indirectly, in chemically induced neoplasia.

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“…Recently, this hypothesis has been supported by the study of Gupta and Dani (1989), who identified N -hydroxy vinyl carbamate and an epoxy derivative of ethyl carbamate as metabolites. Furthermore, 7-(2-oxoethyl)guanine was identified as a DNA adduct in mouse and rat liver after injection of Iabelied ethyl carbamate (Miller and Miller, 1983;Scherer et al, 1986).…”

Section: Dna-adduct Formationmentioning

confidence: 89%

“…In an in vitro study, Gupta and Dani (1989) incubated ethyl carbarnate with microsornes from the liver, 1ung, brain and kidneys of the rat. Three metabolites were found using thin-layer chromatography: N -hydroxyethyl carbamate, N -hydroxy vinyl carbamate, epoxyethyl carbamate, when incubated with lung microsomes but not when incubated with microsomes from other organs (no data on the detection Iimit of the metabolites were given).…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

The carcinogenic potential of ethyl carbamate (urethane): Risk assessment at human dietary exposure levels

Schlatter

Lutz

1990

Food and Chemical Toxicology

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Summary-Ethyl carbamate is found in fermented foods: bread contains 3-15 ng/g, stone-fruit brandies 200-20,000 ngfg, and about one-third of table-wine samples analysed contained more than 10 ng/g. In animals, ethyl carbamate is degraded to C0 2 , H 2 0 and NH 3 , with intermediate formation ofethanol. This degradation has been shown tobe inhibited (postponed) in the mouse by ethanol concentrations in the blood of about 0.15% and higher. A quantitatively minor pathway involves a two-step oxidation of the ethyl group to vinyl carbamate and epoxyethyl carbamate, the postulated electrophilic moiety that reacts with DNA. This reaction is probably the mode of the mutagenic action observed in many cellular and animal systems. The fact that only vinyl carbamate, but not ethyl carbamate, is mutagenic in a standard Ames test is probably because there is insufficient production of the intermediate oxidation product in the standard test. Consistent with this metabolism is the carcinogenic activity of ethyl carbamate in various animal species and in different organs; this activity can be seen even after a single high dose in early life. Quantitative analysis of the total tumour incidences after chronic exposure of rats and mice to 0.1-12.5 mg ethyl carbamate/kg body weightjday in the drinking-water showed a dose-related increase. The main target organs were the mammary gland (female rats and mice having similar susceptibilities) and the Jung (mice only). On the basis of sex-and organ-specific tumour data and with a linear extrapolation to a negligible increase of the lifetime tumour incidence by 0.0001% ( one additional tumour in one milüon individuals exposed for life), a "virtually safe dose .. of 20 to 80 ng/kg body weight/day was estimated. The daily burden reached under normal dietary habits without alcoholic beverages is in the range of about 20 ng/kg body weightfday. Regular table-wine consumption would increase the risk by a factor of up to five. Regular drinking of 20 to 40 ml stone-fruit brandy per day could raise the calculated lifetime tumour risk to near 0.01%.

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In vitro formation of organ-specific ultimate carcinogens of 4-dimethylaminoazobenzene and urethan by microsomes

Cited by 18 publications

References 2 publications

Oxidative DNA Damage Induced by an N‐Hydroxy Metabolite of Carcinogenic 4‐Dimethylaminoazobenzene

Oxidative DNA Damage Induced by an N‐Hydroxy Metabolite of Carcinogenic 4‐Dimethylaminoazobenzene

Increased Susceptibility of Vault Poly(ADP-Ribose) Polymerase–Deficient Mice to Carcinogen-Induced Tumorigenesis

The carcinogenic potential of ethyl carbamate (urethane): Risk assessment at human dietary exposure levels

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