Induction of the hepatic mixed-function oxidases by Arochlor 1254 in the hamster: comparison of Arochlor-induced rat and hamster preparations in the activation of pre-carcinogens in the Ames test

Hyde, Robert J.; Smith, J.E.; Ioannides, Costas

doi:10.1093/mutage/2.6.477

Cited by 15 publications

(4 citation statements)

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“…2-(Acetylamino)fluorene can also be significantly activated by cytosolic fractions (7), and for this reason the mutagenicity of these two chemicals was studied using both microsomal and cytosolic fractions. 2-(Acetylamino)fluorene was a potent mutagen, a clear mutagenic response seen in the presence of control and Aroclor 1254-induced microsomes confirming many previous findings where S9 preparations were used (35,36). Similarly, a clear, but less pronounced, mutagenic response was observed in the presence of control and Aroclor 1254-induced cytosol, in accordance with our previous studies (7).…”

Section: Discussionsupporting

confidence: 92%

“…Furthermore, it also stimulated its cytosolic activation, the maximum effect being observed at the dose of 5 mg/kg. The much higher mutagenic response observed when Aroclor 1254-induced microsomes were used as activation systems is undoubtedly due to the much higher degree of P4501A induction (35). Conversely, 4-(acetylamino)fluorene failed to induce its own cytosolic activation, and its microsomal activation was only slightly increased.…”

Section: Discussionmentioning

confidence: 99%

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The mutagenicity and interactions of 2- and 4-(acetylamino)fluorene with cytochrome P450 and the aromatic hydrocarbon receptor may explain the difference in their carcinogenic potency

Ioannides¹,

Cheung²,

Wilson³

et al. 1993

Chem. Res. Toxicol.

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A study has been undertaken to identify the properties of 2-(acetylamino)fluorene which render it carcinogenic, in contrast to the 4-isomer, the carcinogenic potential of which is, at best, very weak. Compared to the 4-isomer, 2-(acetylamino)fluorene was a more potent inducer of cytochrome P450 1A (P450 1A) activity, as exemplified by the O-deethylation of ethoxyresorufin (P450 1A1), the metabolic activation of Glu-P-1 (P450 1A2), and immunoblot analysis. These findings were consistent with the relative affinity of these compounds for the cytosolic aromatic hydrocarbon receptor, determined by the displacement of tetrachlorodibenzo-p-dioxin. In the presence of Aroclor 1254-induced hepatic microsomal and cytosolic preparations 2-(acetylamino)-fluorene elicited a potent mutagenic response in the Ames test whereas the 4-isomer, in both cases, elicited a weak mutagenic response. Molecular orbital calculations of the relative energetics of the nitrenium ions revealed that the ion of the 2-isomer was more stable than the nitrenium ion of 4-(acetylamino)fluorene. Control hepatic microsomal and cytosolic fractions could activate 2-(acetylamino)fluorene to mutagens in the Ames test. Pretreatment of animals with 2-(acetylamino)fluorene enhanced both the microsome- and cytosol-mediated activation. In contrast, microsomal and cytosolic fractions from control animals could not activate 4-(acetylamino)fluorene, but following pretreatment with the compound itself, a weak mutagenic response in the presence of microsomes, but not of cytosol, was evident.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

The mutagenicity and interactions of 2- and 4-(acetylamino)fluorene with cytochrome P450 and the aromatic hydrocarbon receptor may explain the difference in their carcinogenic potency

Ioannides¹,

Cheung²,

Wilson³

et al. 1993

Chem. Res. Toxicol.

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“…Rats can be treated with Aroclor 1254 for two to three days prior to harvesting the liver and preparation of S9. The specific content of many of the drug metabolism enzymes is greatly increased in Aroclor 1254 induced S9 [225,226].…”

Section: Genotoxicitymentioning

confidence: 99%

Gauging Reactive Metabolites in Drug-Induced Toxicity

Eno¹,

Cameron²

2014

CMC

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Over the past decades, it has become abundantly clear that enzymes evolved to detoxify and eliminate foreign chemicals from the body, occasionally generate highly reactive metabolites which have toxicological implications. To decrease the probability of late clinical failure or market withdrawal, there has been an increased prioritization on understanding key metabolic processes that might cause drug interactions or toxicities. Significant advances have been made in the detection of reactive metabolites and in understanding the structure activity relationship. It is now widely accepted that compounds with certain functional groups such as anilines, quinones, hydrazines, thiophenes, furans, acylpropionic acids, and alkynes have a much greater associated risk towards formation of reactive metabolites than compounds that do not contain such "structural alerts". Detection of reactive metabolites is usually done with in vitro assays, which have become more sensitive with advances in mass spectrometry. As an increasingly large number of compounds that form reactive metabolites have been identified, much of the focus has shifted from detection to evaluation of toxicological implication. While there is a disproportionate number of compounds metabolized to reactive metabolites that are associated with drug-induced hepatotoxicity and serious skin toxicities such as toxic endothelial necrolysis and Steven's Johnson syndrome, attempts to predict toxicity based on in vitro testing have been discouraging. In this review we attempt to summarize the experimental options available to evaluate reactive metabolites.

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“…Furthermore, it should be noted that solvents commonly used to dissolve the test agent for addition into the assay system (e.g. DMSO and methanol) can act as competitive inhibitors of certain P450 isoforms such as CYP2E1 [103][104][105], and interfere with the bioactivation of the test chemical.…”

Section: Metabolism and Toxicokinetics Of The Chemicalmentioning

confidence: 99%

Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

Eastmond

2012

Mutation Research/Reviews in Mutation Research

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The determination of whether a chemical induces cancer through a mutagenic or genotoxic mechanism frequently plays an important role in evaluating the risks associated with low dose exposure. Although various approaches are employed for making mode of action decisions, a systematic investigation to identify the major factors that influence these determinations has not been performed. To accomplish this, over 40 chemical risk assessments conducted by U.S. or international regulatory agencies and organizations were reviewed to identify components that had played a significant role, either directly or indirectly, in the decision-making process. The major factors identified included the chemical properties of the agent, its metabolites and degradation products; its metabolism and toxicokinetics; genotoxic effects seen in vivo, particularly in the target organ; structural or metabolic similarities to known mutagenic or nonmutagenic chemicals; characteristics of the tumors induced in the animal bioassays; and the origin of the observed effects. The quality of the data, the specific genotoxic endpoint and its sensitivity to assay conditions and toxicity were also important considerations. In all cases, the authoritative groups used a weight-of-evidence approach and, in most cases where evaluations were conducted by more than one authoritative body, similar conclusions were reached. In summary, a critical evaluation of the data as well as expert judgment is necessary in reaching mechanism of action conclusions. These determinations should be made within the broader context of evaluating the chemical's overall toxicity and carcinogenicity.

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Induction of the hepatic mixed-function oxidases by Arochlor 1254 in the hamster: comparison of Arochlor-induced rat and hamster preparations in the activation of pre-carcinogens in the Ames test

Cited by 15 publications

References 0 publications

The mutagenicity and interactions of 2- and 4-(acetylamino)fluorene with cytochrome P450 and the aromatic hydrocarbon receptor may explain the difference in their carcinogenic potency

The mutagenicity and interactions of 2- and 4-(acetylamino)fluorene with cytochrome P450 and the aromatic hydrocarbon receptor may explain the difference in their carcinogenic potency

Gauging Reactive Metabolites in Drug-Induced Toxicity

Factors influencing mutagenic mode of action determinations of regulatory and advisory agencies

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