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Metabolism of carcinogenic N-nitroso-N-methylaniline by purified cytochromes P450 2B1 and P450 2B2. 1996

M Stiborová, and H Hansíková, and E Frei
Department of Biochemistry, Faculty of Natural Sciences, Charles University, Albertov, Czech Republic.

N-Nitroso-N-methylaniline (NMA) is an esophageal carcinogen in the rat. The in vitro enzymatic metabolism of NMA was investigated using cytochromes P450 2B1 and P450 2B2, isolated from liver microsomes of rats pretreated with phenobarbital (PB), reconstituted with NADPH-cytochrome P450 reductase and dilauroylphosphatidylcholine. Formaldehyde is produced by both cytochromes P450 (P450). NMA is a better substrate for P450 2B1 than for P450 2B2. The maximal velocity (Vmax) values are 3.3 and 1.6 nmol HCHO/min per nmol P450 for P450 2B1 and P450 2B2, respectively. Beside formation of formaldehyde, aniline and p-aminophenol (p-AP) are found to be metabolites formed from NMA by both P450 isoenzymes. P450 2B1 also affords phenol, while none was found with the P450 2B2 isoenzyme. Phenol formation presumably arose from direct alpha-C-hydroxylation of NMA via a benzenediazonium ion (BDI) intermediate. The results suggest strongly that P450 2B1 catalyzes both alpha-C-hydroxylation and denitrosation of NMA while P450 2B2 catalyzes only denitrosation. Therefore, the P450 2B1 isoenzyme participates in the activation of NMA to the ultimate carcinogenic BDI.

UI MeSH Term Description Entries
D009602 Nitrosamines A class of compounds that contain a -NH2 and a -NO radical. Many members of this group have carcinogenic and mutagenic properties. Nitrosamine
D010634 Phenobarbital A barbituric acid derivative that acts as a nonselective central nervous system depressant. It potentiates GAMMA-AMINOBUTYRIC ACID action on GABA-A RECEPTORS, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarizations. Phenemal,Phenobarbitone,Phenylbarbital,Gardenal,Hysteps,Luminal,Phenobarbital Sodium,Phenobarbital, Monosodium Salt,Phenylethylbarbituric Acid,Acid, Phenylethylbarbituric,Monosodium Salt Phenobarbital,Sodium, Phenobarbital
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D000814 Aniline Compounds Compounds that include the aminobenzene structure. Phenylamine,Phenylamines,Anilines,Compounds, Aniline
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001189 Aryl Hydrocarbon Hydroxylases A large group of cytochrome P-450 (heme-thiolate) monooxygenases that complex with NAD(P)H-FLAVIN OXIDOREDUCTASE in numerous mixed-function oxidations of aromatic compounds. They catalyze hydroxylation of a broad spectrum of substrates and are important in the metabolism of steroids, drugs, and toxins such as PHENOBARBITAL, carcinogens, and insecticides. Microsomal Monooxygenases,Xenobiotic Monooxygenases,Hydroxylases, Aryl Hydrocarbon,Monooxygenases, Microsomal,Monooxygenases, Xenobiotic
D013250 Steroid Hydroxylases Cytochrome P-450 monooxygenases (MIXED FUNCTION OXYGENASES) that are important in steroid biosynthesis and metabolism. Steroid Hydroxylase,Steroid Monooxygenases,Hydroxylase, Steroid,Hydroxylases, Steroid,Monooxygenases, Steroid
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D019362 Cytochrome P-450 CYP2B1 A major cytochrome P-450 enzyme which is inducible by PHENOBARBITAL in both the LIVER and SMALL INTESTINE. It is active in the metabolism of compounds like pentoxyresorufin, TESTOSTERONE, and ANDROSTENEDIONE. This enzyme, encoded by CYP2B1 gene, also mediates the activation of CYCLOPHOSPHAMIDE and IFOSFAMIDE to MUTAGENS. BROD,Benzyloxyresorufin O-Dealkylase,CYP2B1,PROD,Pentoxyresorufin O-Dealkylase,7-Benzyloxyresorufin O-Dealkylase,7-Pentylresorufin O-Depentylase,CYP 2B1,Cytochrome P450 2B1,7 Benzyloxyresorufin O Dealkylase,7 Pentylresorufin O Depentylase,Benzyloxyresorufin O Dealkylase,Cytochrome P 450 CYP2B1,O-Dealkylase, Pentoxyresorufin,Pentoxyresorufin O Dealkylase

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