THE INFLUENCE OF 4-ALKYL SUBSTITUENTS ON THE FORMATION AND REACTIVITY OF 2-METHOXY-QUINONE METHIDES - EVIDENCE THAT EXTENDED PI-CONJUGATION DRAMATICALLY STABILIZES THE QUINONE METHIDE FORMED FROM EUGENOL

被引:53
作者
BOLTON, JL [1 ]
COMEAU, E [1 ]
VUKOMANOVIC, V [1 ]
机构
[1] QUEENS UNIV,DEPT CHEM,KINGSTON,ON K7L 3N6,CANADA
关键词
QUINONE METHIDE; EUGENOL; STRUCTURE-REACTIVITY STUDY; GSH; CYTOCHROME P450; HEPATOTOXICITY;
D O I
10.1016/0009-2797(94)03566-Q
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The effects of para-alkyl substituents on both the cytochrome P450-catalyzed oxidation of phenols to quinone methides (QMs; 4-methylene-2,5-cyclohexadien-1-ones), and on the rates of nucleophilic additions to the QMs were investigated. The derivatives of 4-alkyl-2-methoxyphenol studied were 4-methyl (creosol), 4-ethyl, 4-propyl, 4-isopropyl, and 4-allyl (eugenol). The relative reactivities of QMs derived from these phenols with water were 4-methyl > 4-ethyl = 4-propyl > 4-isopropyl > 4-allyl. These variations in rate were rationalized by differences in stabilization of positive charge density at the site of nucleophilic attack. In particular, saturation of the vinyl substituent on eugenol-QM increases the solvolysis rate 100-fold. This effect is presumably due to the loss of the contribution of an additional aromatic resonance structure to the overall resonance hybrid of the QM from 2-methoxy-4-propylphenol. Finally, the kinetic results show that there is a 472-fold difference in reactivity within this series of QMs. The QM glutathione conjugates were synthesized and characterized by H-1-NMR and electrospray mass spectrometry and a HPLC assay was developed to quantify QM formation in rat liver microsomes. The general trend is increasing alkyl substitution at the para position results in more QM; however, in contrast to the large range of reactivities of the QMs observed in the kinetic experiments, the amounts of P450-derived QM GSH adducts varied only by a factor of 3. In particular, similar amounts of the QMs from eugenol and 2-methoxy-4-propylphenol were produced which suggests that the lack of reported hepatotoxicity for the latter phenol in mice depleted of GSH, may be due to the extreme reactivity of 4-propyl-QM that would be rapidly detoxified by hydrolysis. These data suggest that there may be a threshold cytotoxicity level for QMs related to their reactivity which may affect the relative toxicities of 4-alkyl-2-methoxyphenols.
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收藏
页码:279 / 290
页数:12
相关论文
共 27 条
[11]   CHEMICAL REARRANGEMENT OF PHENOL-EPOXIDE METABOLITES OF POLYCYCLIC AROMATIC-HYDROCARBONS TO QUINONE-METHIDES [J].
HULBERT, PB ;
GROVER, PL .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1983, 117 (01) :129-134
[12]   TOXICITY STUDIES ON CLOVE CIGARETTE-SMOKE AND CONSTITUENTS OF CLOVE - DETERMINATION OF THE LD50 OF EUGENOL BY INTRATRACHEAL INSTILLATION IN RATS AND HAMSTERS [J].
LAVOIE, EJ ;
ADAMS, JD ;
REINHARDT, J ;
RIVENSON, A ;
HOFFMANN, D .
ARCHIVES OF TOXICOLOGY, 1986, 59 (02) :78-81
[13]  
MIZUTANI T, 1991, RES COMMUN CHEM PATH, V73, P87
[14]  
MIZUTANI T, 1991, RES COMMUN CHEM PATH, V71, P219
[15]   PULMONARY TOXICITY OF BUTYLATED HYDROXYTOLUENE AND RELATED ALKYLPHENOLS - STRUCTURAL REQUIREMENTS FOR TOXIC POTENCY IN MICE [J].
MIZUTANI, T ;
ISHIDA, I ;
YAMAMOTO, K ;
TAJIMA, K .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1982, 62 (02) :273-281
[17]   METABOLISM AND REACTIONS OF QUINOID ANTICANCER AGENTS [J].
POWIS, G .
PHARMACOLOGY & THERAPEUTICS, 1987, 35 (1-2) :57-162
[18]   THE EFFECT OF BETA-FLUORINE SUBSTITUENTS ON THE RATE AND EQUILIBRIUM-CONSTANTS FOR THE REACTIONS OF ALPHA-SUBSTITUTED 4-METHOXYBENZYL CARBOCATIONS AND ON THE REACTIVITY OF A SIMPLE QUINONE METHIDE [J].
RICHARD, JP ;
AMYES, TL ;
BEI, L ;
STUBBLEFIELD, V .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1990, 112 (26) :9513-9519
[19]   FORMATION OF GLUTATHIONE CONJUGATES DURING OXIDATION OF EUGENOL BY MICROSOMAL FRACTIONS OF RAT-LIVER AND LUNG [J].
THOMPSON, D ;
CONSTANTINTEODOSIU, D ;
EGESTAD, B ;
MICKOS, H ;
MOLDEUS, P .
BIOCHEMICAL PHARMACOLOGY, 1990, 39 (10) :1587-1595
[20]  
THOMPSON D, 1989, J BIOL CHEM, V264, P1016