The role of highly purified cytochrome P-450 isozymes in the activation of 4-aminobiphenyl to mutagenic products in the Ames test

Masson, Hilary A.; Ioannides, Costas; Gorrod, J. W.; Gibson, G. Gordon

doi:10.1093/carcin/4.12.1583

Cited by 33 publications

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“…The present paper describes a unique cytosolic oxygenase activity, apparently of high specific substrate specificity, which is effective in activating certain aromatic amines to mutagenic intermediates in the Ames test. As ringhydroxylated products are largely non-mutagenic [14,15] it may be inferred that this enzyme catalyses the N-hydroxylation of the amine. The requirements for oxygen and reduced dinuc1eotides also support such a role.…”

Section: Discussionmentioning

confidence: 99%

“…(a) Cofactor requirement differs in that NADH can c1early support the microsomal but not the cytosolic activation of 2-aminofluorene. (b) The Aroc1or 1254-induced cytosol failed to convert 4-aminobiphenyl and benzidine to mutagenic intermediates, which are, however, activated by the microsomes [7, 14,16]. It is worth pointing out that 2-aminoanthracene, frequently used as a positive control in mutagenicity studies, is also extensively metabolised by hepatic cytosolic fractions [17].…”

Section: Discussionmentioning

confidence: 99%

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A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

1992

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The contributions of the hepatic microsomal and cytosolic fractions in the metabolic activation of the promutagen 2-aminofluorene into mutagenic intermediates in the Ames test were investigated. Rat hepatic postmitochondrial, microsomal and cytosolic preparations could convert 2-aminofluorene to mutagens, the postmitochondrial preparation being the most and cytosol the least efficient. Pretreatment of the rats with Aroclor 1254 markedly enhanced the cytosol-mediated mutagenicity of the amine but increased microsomal- and postmitochrondrial-mediated mutagenicity only modestly. The cytosol-mediated mutagenicity of 2-aminofluorene was abolished by heat treatment and by incubation with proteinase K, but was unaffected by dialysis emphasising the protein nature of the cytosolic activation system. Oxygen radical generating systems and oxygen radical scavengers did not significantly influence the cytosol-mediated mutagenic response. Similarly incorporation of xanthine or allopurinol into the cytosolic activation system did not modulate the mutagenic response indicating no role for the molybdenum oxygenases. The cytosolic activation of 2-aminofluorene differed from that mediated by the microsomes in cofactor requirement, substrate specificity and sensitivity to DMSO and (+)-catechin. Further centrifugation of the cytosolic fraction to remove any microsomal contamination did not decrease the cytosolic activation of 2-aminofluorene. It is concluded that the hepatic cytosol contains an oxygenase activity capable of activating certain aromatic amines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

1992

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“…It was shown that rubber workers also had increased risk for bladder cancer, attributed largely to exposure to aromatic amines [241,242]. Most aromatic amines are initially activated by Nhydroxylation, mainly in the liver via a cytochrome P-450 catalyzed reaction [243,244].…”

Section: Aromatic Amines and Amidesmentioning

confidence: 99%

Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

211

128

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Drug-metabolizing enzymes are called mixed-function oxidase or monooxygenase and containing many enzymes including cytochrome P450, cytochrome b5, and NADPH-cytochrome P450 reductase and other components. The hepatic cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the metabolism of many drugs and xenobiotics with each cytochrome isozyme responding differently to exogenous chemicals in terms of its induction and inhibition. For example, Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise, Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g. aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites to DNA and proteins are correlated with the induction of cytochrome P450 isozymes. Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the agents, and is subjected to many variables that are a function of this structure, or genetic background, sex, endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and detoxification of xenobiotics and carcinogens have been discussed in the text.

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“…4′-OH-ABP binding to DNA is consistent with this metabolite being mutagenic and/or genotoxic. However, while ABP was shown to be mutagenic in the Ames test supplemented with a cytochrome P-450 activation system, 4′-OH-ABP was not mutagenic (57). That is, 4′-OH-ABP was not activated by cytochrome P-450.…”

Section: Discussionmentioning

confidence: 95%

Transformation and Activation of Benzidine by Oxidants of the Inflammatory Response

Lakshmi

Hsu

Zenser

2003

Chem. Res. Toxicol.

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Aromatic amines, such as benzidine (BZ), initiate bladder cancer in humans. Inflammation/infection play an important role in this cancer. This study was designed to assess the influence of inflammatory oxidants, including reactive nitrogen oxygen species (RNOS), on BZ transformation and activation. RNOS were generated under various conditions and reacted with BZ, and the products were examined by HPLC. Conditions that generate nitrogen dioxide radical, NO(2)(-) + myeloperoxidase + H(2)O(2) and ONOO(-), produced primarily a single new product, which was identified by MS as azobenzidine (AZO-BZ). The myeloperoxidase-catalyzed reaction was inhibited by 1 mM cyanide and did not require NO(2)(-). Chloride (100 mM) reduced the myeloperoxidase reaction by 30% with taurine having little effect. In contrast, conditions that generate N(2)O(3), i.e., NO donor diethylamine (DEA) NONOate, produced two products, which were identified by MS as 4'-OH-4-aminobiphenyl (4'-OH-ABP) and 4-aminobiphenyl (ABP). 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, an oxidant of NO thought to produce NO(2)(*), had a biphasic effect on product formation. At a concentration equal to DEA NONOate, a 5-fold increase in BZ nitrosation was observed, while at higher concentrations nitrosation was greatly diminished and formation of AZO-BZ occurred. Glutathione prevented RNOS transformation of BZ. With MPO and ONOO(-), a new product was formed that cochromatographed with 3-(glutathione-S-yl)BZ. Glutathione also prevented nitrosation of BZ but did not form additional BZ products. HOCl-mediated activation of BZ, 4'-OH-ABP, and ABP to bind DNA was assessed. A higher level of binding was observed at pH 5.5 than pH 7.4. BZ elicited the most binding. More binding was observed at both pH values with 4'-OH-ABP than ABP. Thus, components of the inflammatory response are capable of BZ transformation and activation.

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The role of highly purified cytochrome P-450 isozymes in the activation of 4-aminobiphenyl to mutagenic products in the Ames test

Cited by 33 publications

References 0 publications

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

A cytosolic oxygenase activity involved in the bioactivation of 2-aminofluorene

Drug-Metabolizing Enzymes Mechanisms and Functions

Transformation and Activation of Benzidine by Oxidants of the Inflammatory Response

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