The carcinogenic action of benzidine

Spitz, Sophie; Maguigan, W. H.; Dobriner, Konrad

doi:10.1002/1097-0142(1950)3:5<789::aid-cncr2820030505>3.0.co;2-u

Cited by 151 publications

(35 citation statements)

References 4 publications

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“…lj) therefore represents a false-positive result, especially as this material is reported to give a negative response in the Ames assay . (The significance of this negative result is nonetheless weakened by an earlier report that the parent carcinogen DAB (I) was also negative in this assay in the same laboratory (Ames et al, 1973 Spitz et al, 1950). With this derivative, the spacial proximity of the sulphonic-acid groups to the amino groups would be expected to exert such a marked electronic, steric and hydrogen-binding effect on them that they would be incapable of undergoing or effectively completing the required oxidative activation.…”

Section: Discussionmentioning

confidence: 78%

“…la and b) may be due to augmentation of the metabolie activity of the rat liver 8-9 mix by hamster and other rodent cells' innate capacity for oxidative metabolism (Newbold et al, 1977;Heidelberger, 1976 In an attempt to demonstrate the importance of metabolic detoxification pathways to the response given by an in vitro test, we tested DAB in the cell-transformation assay in the presence of azobenzene (VI). This material, whilst being noncarcinogenic to rats (Spitz et al, 1950) and negative in the present assay (Fig. le) was intended as a substrate for both the Chydroxylase and azoreductase enzymes of the S-9 mix.…”

Section: Discussionmentioning

confidence: 99%

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In vitro evaluation of some derivatives of the carcinogen butter yellow: implications for environmental screening

Ashby¹,

Styles²,

Paton³

1978

Br J Cancer

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Summary. The rat-liver carcinogen 4-dimethylaminoazobenzene (Butter Yellow, DAB) and 12 of its structural analogues have been evaluated in a cell transformation assay. Eight of these analogues have already been tested for carcinogenicity in rats, whilst the remaining 4 are new or hitherto untested. Benzidine and its 3,3' -disulphonic acid derivative have also been evaluated.The in vitro results agree with long-term animal data for 8 compounds but disagree in finding DAB-4'-sulphonic acid, 4-trifluoromethyl-DAB and 4-diethylaminoazobenzene positive. Possible reasons for these divergencies are discussed. It is concluded that 9-phenylazojulolidine and N-methyl-5-phenylazoindoline have carcinogenic potential and that 3,5-dimethyl-4-aminoazobenzene and 4-aminoazobenzene-4'-sulphonic acid are likely to prove non-carcinogenic.Addition of azobenzene to the in vitro assay medium increases the transforming potency of DAB 25-fold. It is suggested that it acts as a competitive substrate for one of the enzymes that detoxify DAB, and that this effect is related to that produced by norharman.Sulphonic-acid derivatives of established carcinogens are usually inactive. The basis of this effect has been investigated, and it is suggested that it can operate by two separate mechanisms.It has been established that this assay cannot be relied upon to predict the in vivo potency of a carcinogen. Consideration has been given to possible changes which could be made to the liver activation system (the S -9 mix) currently used in in vitro carcinogenicity assays, and a diagram is presented of the metabolic conversions of a comzpound which might lead to mutation or tumour formation. This enables the term potential carcinogen to be accurately defined, and indicates a possible difference between absolute non-carcinogens and compounds which fail to produce cancer in vivo.

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Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of some derivatives of the carcinogen butter yellow: implications for environmental screening

Ashby¹,

Styles²,

Paton³

1978

Br J Cancer

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“…Benzidine (BZ) has been shown to induce tumors at various sites in laboratory animals (1,2). The major target organ in the rat and mouse is the liver, whereas tumors of the bladder are observed in dogs.…”

Section: Introductionmentioning

confidence: 99%

Binding of benzidine, N-acetylbenzidine, N, N'-diacetylbenzidine and Direct Blue 6 to rat liver DNA.

Martin¹,

Beland²,

Kennelly³

et al. 1983

Environ Health Perspect

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Studies were performed to assess covalent binding of [3H]benzidine, [14C]N-acetylbenzidine, [14C]N, N'-diacetylbenzidine, and the benzidine-derived azo dye Direct Blue 6 to rat hepatic DNA. Following IP injection into male Sprague-Dawley rats, benzidine and N-acetylbenzidine bound to liver DNA to yield the same adduct: N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. The isomeric N-(deoxyguanosin-8-yl)-N-acetylbenzidine and the deacetylated adduct N-(deoxyguanosin-8-yl) benzidine were also synthesized, but neither of these adducts was detected in vivo. Injection of N,N'-diacetylbenzidine resulted in only barely detectable binding which was insufficient for adduct analysis. [3H]Direct Blue 6 was administered to male Wistar rats either by IP injection or by gavage. In both instances, Direct Blue 6 bound covalently to liver DNA; however, binding occurred at a much higher level in the IP injected animals. With IP injected animals, high pressure liquid chromatographic analysis indicated that approximately 70% of the radioactivity was associated with N-(deoxyguanosin-8-yl) benzidine.

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“…(5) (Griswold et al, 1966) 3-methyl-4-aminobiphenyl (6) (Walpole and Williams, 1958;Miller, 1962) and ortho-tolidine (7) (Spitz et al, 1950) each elicit a carcinogenic effect in laboratory animals equal to or greater than that observed for their respective parent compounds, whilst 3-methyl-4-dimethylaminoazobenzene (8), the analogous derivative of the carcinogen 4-dimethylaminoazobenzene (DAB), is inactive (Miller andMiller, 1948, 1953b). The apparent unpredictability of the outcome ofisosteric molecular modification of known carcinogens is illustrated by 4-acetamidobiphenyl (9) (WHO/IARC, 1972; Walpole and Williams, 1958) and its methylene-bridged analogue 2-acet-…”

mentioning

confidence: 99%

“…Despite these examples, there does exist a general trend towards non-carcinogenicity when a carcinogen of this and other classes is ring-substituted with a polar or lipophobic group, such as hydroxy (OH) or sulphonic acid group . This is illustrated by the sulphonic acids (27) (Spitz et al, 1950) (28) (Rossner, 1937) (29) (Windaus and Rennhak, 1937) and (30) (Kinosita, 1937), which are all non-carcinogenic derivatives of established carcinogens. It is possible that 2 separate mechanisms may be operating to render Compounds (27)-(30) non-carcinogenic.…”

mentioning

confidence: 99%

Appendix I. Structural analysis as a means of predicting carcinogenic potential

Ashby¹

1978

Br J Cancer

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The carcinogenic action of benzidine

Cited by 151 publications

References 4 publications

In vitro evaluation of some derivatives of the carcinogen butter yellow: implications for environmental screening

In vitro evaluation of some derivatives of the carcinogen butter yellow: implications for environmental screening

Binding of benzidine, N-acetylbenzidine, N, N'-diacetylbenzidine and Direct Blue 6 to rat liver DNA.

Appendix I. Structural analysis as a means of predicting carcinogenic potential

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