Interaction with the Aromatic Hydrocarbon Receptor, CYP1A Induction, and Mutagenicity of a Series of Diaminotoluenes: Implications for Their Carcinogenicity

Cheung, Yen-Ling; Snelling, Jacqueline; Mohammed, Nagat; Gray, Tim J.B.; Ioannides, Costas

doi:10.1006/taap.1996.0159

Cited by 38 publications

(26 citation statements)

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“…For both the nitroaromatics and aromatic amines, metabolic activation is required for mutagenic and carcinogenic activity, and the initial step in the activation process is oxidation of the amine function to a hydroxylamine intermediate. This hydroxylation is catalyzed primarily by CYP1A2 [37,38], and many of the amines activated by CYP1A2 also selectively induce it [53][54][55].…”

Section: Discussionmentioning

confidence: 99%

Induction of mouse cytochrome P450 2B enzymes by amine metabolites of musk xylene: Contribution of microsomal enzyme induction to the hepatocarcinogenicity of musk xylene

et al. 1997

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Musk xylene (MX) is a synthetic nitromusk perfume ingredient that, although uniformly negative in genotoxicity testing, causes liver tumors in B6C3F1 mice. MX is also capable of inducing cytochrome P450 enzymes in a manner similar to that of phenobarbital (PB), which suggests that epigenetic mechanisms may be involved in the carcinogenic response. At the same time, MX is metabolized in vivo by nitroreduction, a reaction catalyzed by intestinal flora that yields aromatic amine metabolites. These amine metabolites are also capable of inactivating CYP2B10, the major cytochrome P450 enzyme induced by MX treatment. In the study reported here, the monoamine metabolites of MX, o- and p-NH2-MX, were evaluated for their potential to induce CYP2B10 and CYP1A2 mRNAs. Northern blot analyses indicated that both amines markedly induced CYP2B10 mRNA, whereas CYP1A2 mRNA, the enzyme implicated in the bioactivation of aromatic amines and frequently induced by aromatic amines, was induced only slightly, a response that was not different from that seen with PB. Induction of CYP2B10 mRNA suggested that the amine metabolites may contribute to the enzyme induction profile seen with MX treatment. To test this hypothesis, mice were treated with broad-spectrum antibiotics (neomycin, tetracycline, and bacitracin) to eliminate the intestinal flora and prevent formation of o- and p-NH2-MX. In antibiotic-treated mice treated with MX (200 mg/kg) for 4 d, no evidence of microsomal enzyme induction was observed, including no increases in liver weight, total cytochrome P450 content, or CYP2B protein levels. These results indicate that the amine metabolites of MX are responsible for the enzyme induction seen after MX administration. Thus, the biochemical and molecular effects of amine metabolites of MX are markedly different from those of other aromatic amines but very similar to those of PB. Therefore, it appears that MX is a non-genotoxic chemical that may cause mouse liver tumors in a manner analogous to that of PB.

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Section: Discussionmentioning

confidence: 99%

Induction of mouse cytochrome P450 2B enzymes by amine metabolites of musk xylene: Contribution of microsomal enzyme induction to the hepatocarcinogenicity of musk xylene

et al. 1997

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“…Most of the toxicity studies have attempted to elucidate the differences in mechanism of action between 2,4-TDA and the inactive 2,6-TDA. In a liver microsomal system, 2,4-TDA was mutagenic, induced CYP 1A, and bound to the Ah receptor, whereas the other isomers were much less active (215). In vivo, 2,4-TDA had twice the mutagenic activity of 2,6-TDA, which showed values like the controls (229).…”

Section: Toxic Effectsmentioning

confidence: 95%

Aromatic Nitro and Amino Compounds

Bingham¹,

McGowan²

2012

Patty's Toxicology

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Logically, aromatic nitro and amino compounds should be discussed together because their toxic responses are often similar due to a common metabolic intermediate. Synthetically, amines are generally derived from nitro compounds, but in some cases nitro compounds can be prepared through amines when other methods fail to afford specific compounds. There are good and bad attributes to these types of compounds. Some act as sensitizers and contingent on physical properties may be absorbed through the skin or mucous membranes. They may also cause methemoglobinemia, depending on such factors as the structure and the particular organism. Some members of this class are known as animal and human carcinogens; for humans, the urinary bladder is the most prominent target organ. Nevertheless, these compounds and their derivatives have enlivened our world through their use as dyestuff intermediates or as photographic chemicals, they alleviate pain as components of widely used analgesics, and they cushion or insulate us through their use in flexible and rigid foams. Other important uses include production of pesticides, including herbicides and fungicides, as ingredients in adhesives, paints and coatings, antioxidants, explosives, optical brighteners, rubber ingredients, and as intermediates in many other products.

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“…In most cases, the chemical is unable to interact directly with DNA, but may readily interact through metabolically formed reactive intermediates generated within the living organism. 13 The four possible isomers differ in their carcinogenic potential. 2,4-TDA has been described as a moderate carcinogen, inducing tumors in the livers of both rats and mice.…”

Section: ·1 Tda and Their Isomersmentioning

confidence: 99%

“…17 2,6-TDA is classified as a noncarcinogen, having failed to induce tumors in both rats and mice, 16 but in the Ames test, the presence of an activation system, it elicits a mutagenic response. 17 Cheung et al 13 reported that 2,4-TDA is readily Nhydroxylated by hepatic microsomes.…”

Section: ·1 Tda and Their Isomersmentioning

confidence: 99%

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2,4-Toluene Diamines—Their Carcinogenicity, Biodegradation, Analytical Techniques and an Approach towards Development of Biosensors

et al. 2001

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Interaction with the Aromatic Hydrocarbon Receptor, CYP1A Induction, and Mutagenicity of a Series of Diaminotoluenes: Implications for Their Carcinogenicity

Cited by 38 publications

References 0 publications

Induction of mouse cytochrome P450 2B enzymes by amine metabolites of musk xylene: Contribution of microsomal enzyme induction to the hepatocarcinogenicity of musk xylene

Induction of mouse cytochrome P450 2B enzymes by amine metabolites of musk xylene: Contribution of microsomal enzyme induction to the hepatocarcinogenicity of musk xylene

Aromatic Nitro and Amino Compounds

2,4-Toluene Diamines—Their Carcinogenicity, Biodegradation, Analytical Techniques and an Approach towards Development of Biosensors

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