METABOLISM OF CARCINOGENIC N-NITROSO-N-METHYLANILINE BY PURIFIED CYTOCHROMES P450 2B1 AND P450 2B2

Citation
M. Stiborova et al., METABOLISM OF CARCINOGENIC N-NITROSO-N-METHYLANILINE BY PURIFIED CYTOCHROMES P450 2B1 AND P450 2B2, Cancer letters, 110(1-2), 1996, pp. 11-17
Citations number
34
Categorie Soggetti
Oncology
Journal title
ISSN journal
03043835
Volume
110
Issue
1-2
Year of publication
1996
Pages
11 - 17
Database
ISI
SICI code
0304-3835(1996)110:1-2<11:MOCNBP>2.0.ZU;2-A
Abstract
N-Nitroso-N-methylaniline (NMA) is an esophageal carcinogen in the rat , The in vitro enzymatic metabolism of NMA was investigated using cyto chromes P450 2B1 and P450 2B2, isolated from liver microsomes of rats pretreated with phenobarbital (PB), reconstituted with NADPH-cytochrom e P450 reductase and dilauroylphosphatidylcholine. Formaldehyde is pro duced by both cytochromes P350 (P450). NMA is a better substrate for P 450 2B1 than for P450 2B2. The maximal velocity (V-max) values are 3.3 and 1.6 nmol HCHO/min per nmol P450 for P450 2B1 and P450 2B2, respec tively. Beside formation of formaldehyde, aniline and p-aminophenol (p -AP) are found to be metabolites formed from NMA by both P450 isoenzym es. P450 2B1 also affords phenol, while none was found with the P450 2 B2 isoenzyme. Phenol formation presumably arose from direct alpha-C-hy droxylation of NMA via a benzenediazonium ion (BDI) intermediate. The results suggest strongly that P450 2B1 catalyzes both alpha-C-hydroxyl ation and denitrosation of NMA while P450 2B2 catalyzes only denitrosa tion. Therefore, the P450 2B1 isoenzyme participates in the activation of NMA to the ultimate carcinogenic BDI.