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The binding affinity of carcinogenic N-nitrosodimethylamine and N-nitrosomethylaniline to cytochromes P450 2B4, 2E1 and 3A6 does not dictate the rate of their enzymatic N-demethylation
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SYSNO ASEP 0434973 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název The binding affinity of carcinogenic N-nitrosodimethylamine and N-nitrosomethylaniline to cytochromes P450 2B4, 2E1 and 3A6 does not dictate the rate of their enzymatic N-demethylation Tvůrce(i) Šulc, Miroslav (MBU-M) RID, ORCID
Hodek, P. (CZ)
Stiborová, M. (CZ)Zdroj.dok. General Physiology and Biophysics. - : AEPress - ISSN 0231-5882
Roč. 29, č. 2 (2010), s. 175-185Poč.str. 11 s. Jazyk dok. eng - angličtina Země vyd. SK - Slovensko Klíč. slova Cytochrome P450 ; CYP2B4 ; CYP2E1 Vědní obor RIV CE - Biochemie CEZ AV0Z50200510 - MBU-M (2005-2011) UT WOS 000279094900008 DOI https://doi.org/10.4149/gpb_2010_02_175 Anotace The interaction of carcinogenic N-nitrosodimethylamine (NDMA) and N-nitrosomethylaniline (NMA) with cytochromes P450 (CYP), CYP2B4, CYP2E1 and CYP3A6, and their metabolism by these enzymes reconstituted with NADPH-CYP reductase in liposomes were studied. Using the difference spectroscopy, the lowest values of spectral dissociation constants (K(S)) of the binary complex of NDMA and NMA with the enzyme were found for CYP2E1. Both N-nitrosamines bind to the heme iron atom as ligands. On the contrary, the binding of NDMA and NMA to CYP2B4 gives the type I spectra. NDMA is bound to CYP3A6 analogously as to CYP2B4, whereas no difference spectra were acquired with NMA and CYP3A6. All tested CYPs oxidize NDMA and NMA. CYP2E1 exhibits the lowest K(m) values, 7.5 and 5.0 mu mol/l for NDMA and NMA, respectively, and for CYP3A6 we found 30.0 and 10.0 mu mol/l for NDMA and NMA, respectively, while CYP2B4 exhibits the lowest affinity for both carcinogens.. In spite of different binding affinities of NDMA and NMA, the values of V(max) for their oxidation were, however, similar for all tested CYPs. The results demonstrate that investigations utilizing several enzymatic approaches are necessary to properly evaluate the mechanism and efficiency of NDMA and NMA oxidation by CYPs in vitro. Pracoviště Mikrobiologický ústav Kontakt Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Rok sběru 2015
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