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THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT

1. Eighteen known or possible metabolites of the hepatic carcinogen 4- (or p-) dimethylaminoazobenzene were tested for carcinogenic activity in the rat. Of these compounds only 4-monomethylaminoazobenzene, a known metabolite, proved to be active. Eight compounds, which appear to be metabolites of th...

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Autores principales: Miller, J. A., Miller, E. C.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 1948
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2135766/
https://www.ncbi.nlm.nih.gov/pubmed/18911175
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author Miller, J. A.
Miller, E. C.
author_facet Miller, J. A.
Miller, E. C.
author_sort Miller, J. A.
collection PubMed
description 1. Eighteen known or possible metabolites of the hepatic carcinogen 4- (or p-) dimethylaminoazobenzene were tested for carcinogenic activity in the rat. Of these compounds only 4-monomethylaminoazobenzene, a known metabolite, proved to be active. Eight compounds, which appear to be metabolites of the dye, were inactive; these included 4-aminoazobenzene, 4'-hydroxy-4-monomethylaminoazobenzene, 4'-hydroxy-4-aminoazobenzene, N-methyl-p-phenylenediamine, p-phenylenediamine, aniline, p-aminophenol, and o-aminophenol. Nine compounds which may possibly be metabolites also were inactive; these compounds were 4'-hydroxy-, 3'-hydroxy-, and 2'-hydroxy-4-dimethylaminoazobenzene, 4-formylaminoazobenzene, 4-hydroxyazobenzene, 2, 4'-diamino-5-dimethylaminodiphenyl, 3-dimethylaminocarbazole, N,N-dimethyl-p-phenylenediamine, and p-hydroquinone. A mixture of 9 known and possible metabolites was also found to be inactive. These data indicate that the primary carcinogen operative in tumor formation by 4-dimethylaminoazobenzene is probably an azo dye closely related to the parent carcinogen. This conclusion is supported by recent work from this laboratory which indicates that the primary carcinogen consists of either or both of the protein-bound dyes found in the liver, i.e. 4-monomethylaminoazobenzene and an unidentified polar aminoazo dye, and that the formation of bound dye constitutes one of the first steps in this carcinogenic process. 2. The carcinogenic activities of 19 other compounds related to 4-dimethyl-aminoazobenzene were tested to obtain more information on the structural features needed for a 4-aminoazo dye to possess strong activity in the rat. 3'-Methyl-4-monomethylaminoazobenzene and the corresponding dimethylamino derivative were nearly twice as active and 4-ethylmethylaminoazobenzene had the same activity as 4-dimethylaminoazobenzene. As tested 3'-nitro- and 3'-chloro-4-dimethylaminoazobenzene both had about the same activity as 4-dimethylaminoazobenzene; however, since the 3'-nitro derivative was incompletely absorbed its real activity appears to be about 1½ times that of 4-dimethylaminoazobenzene. 2'-Nitro- and 2'-chloro-4-dimethylaminoazobenzene were about one-half to one-third as active and 4'-chloro-4-dimethylaminoazobenzene was approximately one-fourth as active as the parent dye. 3'-Ethoxy-4-dimethylaminoazobenzene and 3-methyl-4-monomethylaminoazobenzene exhibited only slight carcinogenic activity. The following compounds proved inactive: the benzamide of N,N-dimethyl-p-phenylenediamine; the diethyl, monoethyl, benzylmethyl, β-hydroxyethylmethyl, and formyl derivatives of 4-aminoazobenzene on the amino group; and the 3-methyl, 3', 5'-dimethyl, 2',5'-dimethyl, and 2',4'-dimethyl derivatives of 4-dimethylaminoazobenzene. From the available data two conditions appear to be essential if a dye is to possess high activity: (1) at least one methyl group must be attached to the amino group together with the proper second substituent, and (2) the rings must bear either no substituents or carry only certain substituents, preferably in the 3' position. 3. The data on the carcinogenicity of the 2'-, 3'-, or 4'-methyl, chloro, and nitro derivatives of 4-dimethylaminoazobenzene show that the position of these groups determines the carcinogenicity of these compounds to a greater extent than does the type of group. The activity relationship was 3' > 2' > 4'. 4. Primary, secondary, and tertiary aminoazo dyes were determined in the livers and blood of rats fed aminoazo dyes which differed in the substituents on the amino group. The data show that deethylation of 4-diethyl-, 4-monoethyl-, and 4-ethylmethylaminoazobenzene occurs in vivo just as 4-dimethyl- and 4-monomethylaminoazobenzene are demethylated in vivo. However, 4-benzylmethylaminoazobenzene and 4-β-hydroxyethylmethylaminoazobenzene were dealkylated only slightly under similar conditions. 5. The following new compounds are described: 4-ethylmethyl-, 4-monoethyl-, 4-benzylmethyl-, and 4-β-hydroxyethylmethylaminoazobenzene; 4'-hydroxy-, 3-methyl-, and 3'-methyl-4-monomethylaminoazobenzene; 2'-hydroxy-, 3'-hydroxy, 3-methyl-, 3'-ethoxy-, 3', 5'-dimethyl-, 2', 5'-dimethyl-, and 2',4'-dimethyl-4-dimethylaminoazobenzene.
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spelling pubmed-21357662008-04-18 THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT Miller, J. A. Miller, E. C. J Exp Med Article 1. Eighteen known or possible metabolites of the hepatic carcinogen 4- (or p-) dimethylaminoazobenzene were tested for carcinogenic activity in the rat. Of these compounds only 4-monomethylaminoazobenzene, a known metabolite, proved to be active. Eight compounds, which appear to be metabolites of the dye, were inactive; these included 4-aminoazobenzene, 4'-hydroxy-4-monomethylaminoazobenzene, 4'-hydroxy-4-aminoazobenzene, N-methyl-p-phenylenediamine, p-phenylenediamine, aniline, p-aminophenol, and o-aminophenol. Nine compounds which may possibly be metabolites also were inactive; these compounds were 4'-hydroxy-, 3'-hydroxy-, and 2'-hydroxy-4-dimethylaminoazobenzene, 4-formylaminoazobenzene, 4-hydroxyazobenzene, 2, 4'-diamino-5-dimethylaminodiphenyl, 3-dimethylaminocarbazole, N,N-dimethyl-p-phenylenediamine, and p-hydroquinone. A mixture of 9 known and possible metabolites was also found to be inactive. These data indicate that the primary carcinogen operative in tumor formation by 4-dimethylaminoazobenzene is probably an azo dye closely related to the parent carcinogen. This conclusion is supported by recent work from this laboratory which indicates that the primary carcinogen consists of either or both of the protein-bound dyes found in the liver, i.e. 4-monomethylaminoazobenzene and an unidentified polar aminoazo dye, and that the formation of bound dye constitutes one of the first steps in this carcinogenic process. 2. The carcinogenic activities of 19 other compounds related to 4-dimethyl-aminoazobenzene were tested to obtain more information on the structural features needed for a 4-aminoazo dye to possess strong activity in the rat. 3'-Methyl-4-monomethylaminoazobenzene and the corresponding dimethylamino derivative were nearly twice as active and 4-ethylmethylaminoazobenzene had the same activity as 4-dimethylaminoazobenzene. As tested 3'-nitro- and 3'-chloro-4-dimethylaminoazobenzene both had about the same activity as 4-dimethylaminoazobenzene; however, since the 3'-nitro derivative was incompletely absorbed its real activity appears to be about 1½ times that of 4-dimethylaminoazobenzene. 2'-Nitro- and 2'-chloro-4-dimethylaminoazobenzene were about one-half to one-third as active and 4'-chloro-4-dimethylaminoazobenzene was approximately one-fourth as active as the parent dye. 3'-Ethoxy-4-dimethylaminoazobenzene and 3-methyl-4-monomethylaminoazobenzene exhibited only slight carcinogenic activity. The following compounds proved inactive: the benzamide of N,N-dimethyl-p-phenylenediamine; the diethyl, monoethyl, benzylmethyl, β-hydroxyethylmethyl, and formyl derivatives of 4-aminoazobenzene on the amino group; and the 3-methyl, 3', 5'-dimethyl, 2',5'-dimethyl, and 2',4'-dimethyl derivatives of 4-dimethylaminoazobenzene. From the available data two conditions appear to be essential if a dye is to possess high activity: (1) at least one methyl group must be attached to the amino group together with the proper second substituent, and (2) the rings must bear either no substituents or carry only certain substituents, preferably in the 3' position. 3. The data on the carcinogenicity of the 2'-, 3'-, or 4'-methyl, chloro, and nitro derivatives of 4-dimethylaminoazobenzene show that the position of these groups determines the carcinogenicity of these compounds to a greater extent than does the type of group. The activity relationship was 3' > 2' > 4'. 4. Primary, secondary, and tertiary aminoazo dyes were determined in the livers and blood of rats fed aminoazo dyes which differed in the substituents on the amino group. The data show that deethylation of 4-diethyl-, 4-monoethyl-, and 4-ethylmethylaminoazobenzene occurs in vivo just as 4-dimethyl- and 4-monomethylaminoazobenzene are demethylated in vivo. However, 4-benzylmethylaminoazobenzene and 4-β-hydroxyethylmethylaminoazobenzene were dealkylated only slightly under similar conditions. 5. The following new compounds are described: 4-ethylmethyl-, 4-monoethyl-, 4-benzylmethyl-, and 4-β-hydroxyethylmethylaminoazobenzene; 4'-hydroxy-, 3-methyl-, and 3'-methyl-4-monomethylaminoazobenzene; 2'-hydroxy-, 3'-hydroxy, 3-methyl-, 3'-ethoxy-, 3', 5'-dimethyl-, 2', 5'-dimethyl-, and 2',4'-dimethyl-4-dimethylaminoazobenzene. The Rockefeller University Press 1948-01-31 /pmc/articles/PMC2135766/ /pubmed/18911175 Text en Copyright © Copyright, 1948, by The Rockefeller Institute for Medical Research New York This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Article
Miller, J. A.
Miller, E. C.
THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT
title THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT
title_full THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT
title_fullStr THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT
title_full_unstemmed THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT
title_short THE CARCINOGENICITY OF CERTAIN DERIVATIVES OF p-DIMETHYLAMINOAZOBENZENE IN THE RAT
title_sort carcinogenicity of certain derivatives of p-dimethylaminoazobenzene in the rat
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2135766/
https://www.ncbi.nlm.nih.gov/pubmed/18911175
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