MECHANISM OF THE MICROSOMAL DEMETHYLATION OF 1-ARYL-3,3-DIMETHYLTRIAZENES

被引：5

作者：

ILEY, J

RUECROFT, G

机构：

[1] Physical Organic Chemistry Research Group, Chemistry Department, The Open University, Milton Keynes

来源：

BIOCHEMICAL PHARMACOLOGY | 1990年 / 40卷 / 09期

关键词：

D O I：

10.1016/0006-2952(90)90244-F

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The metabolism of 1-aryl-3,3-dimethyltriazenes by phenobarbital-induced rat liver microsomes results in the formation of 1-aryl-3-methyltriazenes and formaldehyde. Intermolecular kinetic deuterium isotope effects for the reaction are found to be 1.0 (±0.03) in both Vmax and Vmax/Km respectively. The intramolecular kinetic deuterium isotope effects in Vmax and Vmax/Km are found to be 4.8 (±0.05). There is no correlation of Vmax or Vmax/Km with calculated ionization potentials of the triazenes. For 3-ethyl-3-methyltriazene comparison of values of Vmax and Vmax/Km for ethyl VS methyl loss give rise to values of 3.68 in Vmax and 2.02 in Vmax/Km. Thus, loss of an ethyl group is favoured. The results are discussed in terms of a mechanism in which the triazene undergoes direct hydrogen atom abstraction to form a carbon centred radical. This radical subsequently forms a hydroxymethyltriazene that collapses to formaldehyde and a monomethyltriazene. © 1990.

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页码：2123 / 2128

页数：6

相关论文

共 30 条

[1] MECHANISM OF CYTOCHROME-P-450 CATALYSIS - MECHANISM OF N-DEALKYLATION AND AMINE OXIDE DEOXYGENATION [J].

BURKA, LT ;

GUENGERICH, FP ;

WILLARD, RJ ;

MACDONALD, TL .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1985, 107 (08) :2549-2551

[2] TRIAZENE DRUG METABOLITES - BASE-CATALYZED FORMATION OF N-ALKYLTRIAZENES FROM N-HYDROXYMETHYL-N-ALKYLTRIAZENES [J].

CHENG, SC ;

FERNADES, L ;

ILEY, J ;

ROSA, E .

TETRAHEDRON LETTERS, 1985, 26 (12) :1557-1560

[3] TUMOR INHIBITORY TRIAZENES - STRUCTURAL REQUIREMENTS FOR AN ACTIVE METABOLITE [J].

CONNORS, TA ;

GODDARD, PM ;

MERAI, K ;

ROSS, WCJ ;

WILMAN, DEV .

BIOCHEMICAL PHARMACOLOGY, 1976, 25 (03) :241-246

[4]

FERNANDES MLS, 1987, THESIS U LISBOA LISB

[5] THE RATE OF N-DEMETHYLATION OF N,N-DIMETHYLANILINES AND N-METHYLANILINES BY RAT-LIVER MICROSOMES IS RELATED TO THEIR 1ST IONIZATION-POTENTIAL, THEIR LIPOPHILICITY AND TO A STERIC BULK FACTOR [J].

GALLIANI, G ;

NALI, M ;

RINDONE, B ;

TOLLARI, S ;

ROCCHETTI, M ;

SALMONA, M .

XENOBIOTICA, 1986, 16 (06) :511-517

[6] STRUCTURE REACTIVITY RELATIONSHIPS IN THE MICROSOMAL OXIDATION OF TERTIARY-AMINES [J].

GALLIANI, G ;

RINDONE, B ;

DAGNINO, G ;

SALMONA, M .

EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, 1984, 9 (04) :289-293

[7] STUDIES OF THE MODE OF ACTION OF ANTI-TUMOR TRIAZENES AND TRIAZINES .2. INVESTIGATION OF THE SELECTIVE TOXICITY OF 1-ARYL-3,3-DIMETHYLTRIAZENES [J].

GESCHER, A ;

HICKMAN, JA ;

SIMMONDS, RJ ;

STEVENS, MFG ;

VAUGHAN, K .

BIOCHEMICAL PHARMACOLOGY, 1981, 30 (01) :89-93

[8] INVESTIGATION ON OXIDATIVE N-DEMETHYLATION OF ARYL TRIAZENES INVITRO [J].

GIRALDI, T ;

NISI, C ;

SAVA, G .

BIOCHEMICAL PHARMACOLOGY, 1975, 24 (19) :1793-1797

[9] TRIAZENE METABOLISM .1. THE EFFECT OF SUBSTITUENTS IN THE ARYL GROUP ON THE KINETICS OF ENZYME-CATALYZED N-DEMETHYLATION OF 1-ARYL-3,3-DIMETHYLTRIAZENES [J].

GODIN, JRP ;

VAUGHAN, K ;

RENTON, KW .

CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 1981, 59 (12) :1234-1238

[10] DETERMINATION OF PROTEIN - MODIFICATION OF LOWRY METHOD THAT GIVES A LINEAR PHOTOMETRIC RESPONSE [J].

HARTREE, EF .

ANALYTICAL BIOCHEMISTRY, 1972, 48 (02) :422-&