Pseudoenzymatic reduction of N-hydroxy-2-acetylaminofluorene to 2-acetylaminofluorene mediated by cytochrome P450

Kawa, Shigeyuki; Takekawa, Koji; Sugihara, Kazumi; Tatsumi, Kiyoshi; Ohta, Shigeru

doi:10.1093/carcin/20.2.347

Cited by 4 publications

(2 citation statements)

References 18 publications

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“…Activation of 2-acetylaminofluorene (2-AAF) proceeds through N-hydroxylation which is catalyzed exclusively by cytochromes P-448 [249][250][251], confirming previous observations where antibodies to cytochromes P-448, but not PBcytochromes P-450, decreased the Nhydroxylation and covalent binding of the carcinogen [252][253][254]. Pretreatment of animals with 2-AAF or MC increases the N-hydroxylation of the amide, and increases the cytochromes P-448 content as determined by EROD activity [255,256].…”

Section: Metabolic Activation Of 2-acetylaminofluorenementioning

confidence: 99%

“…Furthermore, monoclonal antibodies to MCinduced cytochromes P-448 inhibited the Nhydroxylation of 2-AAF [257], and the mutagenicity of 2-AAF was inhibited 60% by antibodies to cytochrome P450 3A4 but only 35% by antibodies to cytochrome P-450. Nhydroxylation of acetylaminofluorene occurs to the greatest extent in the liver and is catalyzed by a cytochrome P-450 and NADPH-generating system in the endoplasmic reticulum [251,258]. A major fraction of N-hydroxy-AFF is converted to its 0glucuronide, which is excreted in the bile and urine [259,260,261].…”

Section: Metabolic Activation Of 2-acetylaminofluorenementioning

confidence: 99%

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Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

213

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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Section: Metabolic Activation Of 2-acetylaminofluorenementioning

confidence: 99%

Section: Metabolic Activation Of 2-acetylaminofluorenementioning

confidence: 99%

Drug-Metabolizing Enzymes Mechanisms and Functions

Sheweita

2000

CDM

213

128

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Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones

Nicolescu

Comeau

Hill

et al. 2007

Toxicology and Applied Pharmacology

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Enzymatic and non-enzymatic reduction of brucine N -oxide by aldehyde oxidase and catalase

et al. 2001

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1. Brucine N-oxide was reduced by aldehyde oxidase in rabbit liver cytosol in the presence of an electron donor, 2-hydroxypyrimidine, under anaerobic conditions. The flavoprotein purified from rabbit liver exhibited significant reductase activity in the presence of electron donors. 2. Brucine N-oxide was also reduced by rabbit liver cytosol and blood in the presence of both a reduced pyridine nucleotide and FAD under anaerobic conditions. The N-oxide reductase activities were inhibited by carbon monoxide and air. However, these activities were not abolished whe n liver cytosol and blood were boiled. Rabbit erythrocytes exhibited the reductase activity, but not plasma. 3. When liver cytosol or blood was separated by DEAE-cellulose column chromatography, the fractions with the reducing activity in the presence of both NADH and FAD also showed catalase activity. 4. Catalase catalysed the brucine N-oxide reduction in the presence of both NAD(P)H and FAD. Hematin also exhibited the reductase activity in the presence of both NAD(P)H and FAD. Photochemically reduced FAD was effective in the reduction instead of NAD(P)H and FAD. 5. Bricine N-oxide reduction proceeds via two routes in liver cytosol and blood. One is enzymatic reduction by aldehyde oxidase; the other is non-enzymatic reduction catalysed by the haem group of catalase in the presence of reduced flavin.

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Pseudoenzymatic reduction of N-hydroxy-2-acetylaminofluorene to 2-acetylaminofluorene mediated by cytochrome P450

Cited by 4 publications

References 18 publications

Drug-Metabolizing Enzymes Mechanisms and Functions

Drug-Metabolizing Enzymes Mechanisms and Functions

Aryl radical involvement in amiodarone-induced pulmonary toxicity: Investigation of protection by spin-trapping nitrones

Enzymatic and non-enzymatic reduction of brucine N -oxide by aldehyde oxidase and catalase

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