o-Quinone Isomerization Mechanism
Chem. Res. Toxicol., Vol. 9, No. 1, 1996 113
deuterium isotope effects on enolization reactions have
been determined to be in the range of kH/kD ) 3-6 (19).
Thus the isotope effect on the base-catalyzed enolization
of 2,4-dimethyl-3-pentanone is kH/kD ) 5.5, 35 °C (20).
The kinetic deuterium isotope effect on the isomerization
of the QM, 9-hydroxy-1,10-anthraquinone 1-methide to
the p-quinone, 1-methylanthraquinone, has been esti-
mated to be kH/kD ) 3.0 ( 0.1 (21). In the present study,
the isotope effect on the reverse reaction (isomerization
of o-quinone to QM) is also in this range (kH/kD ) 5.5 (
0.6, 37 °C), which is consistent with the proposed mech-
anism shown in Figure 5.
Refer en ces
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At physiological pH under conditions of low buffer base
concentration, the isomerization of PQ to the P-QM is a
minor metabolic pathway. Other competing reactions
probably dominate in vivo, including successive reduction
of PQ to the semiquinone radical and catechol as well as
the formation of dimeric products. This is probably the
case for most o-quinones with relatively long lifetimes
where isomerization is not favored by the increased
acidity of the benzyl hydrogens. For example, the o-
quinones of hydroxychavicol and 4-cinnamylcatechol
isomerize rapidly to QMs because of the vinyl and
cinnamyl substituents R to the benzyl group stabilizing
negative charge development in the transition state (6).
The present studies indicate, however, that if the o-
quinone is formed in the presence of residues on biopoly-
mers with the ability to act as base catalysts, the
isomerization mechanism could generate a significant
amount of the highly electrophilic QMs. If this reaction
occurs in the vicinity of DNA, QM-mediated DNA alky-
lation could occur, leading to initiation of the carcinogenic
process. Potentially, both quinoids could alkylate DNA;
however, as QMs are considerably more reactive than
o-quinones (3), they are more likely to be the ultimate
DNA modification agents. In support of this, we have
recently shown that the QMs formed from the synthetic
antioxidant butylated hydroxytoluene (BHT) alkylate calf
thymus DNA (22).
(14) Saul, S. J ., and Sugumaran, M. (1990) 4-Alkyl-o-quinone/2-
hydroxy-p-quinone methide isomerase from the larval hemolymph
of Sarcophaga bullata. I. Purification and characterization of
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of drugs and xenobiotics: Implications for drug design. Adv. Drug
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In conclusion, data have been presented on the general
base-catalyzed mechanism of isomerization of 4-propyl-
o-quinone to its tautomeric p-quinone methide. The data
suggest that if this is an undesirable metabolic path-
way in vivo, substitution of protium(s) for deuterium(s)
at benzyl positions could result in metabolic switching
due to the substantial isotope effect on the isomeriza-
tion reaction. The issue of switching metabolism to a
more benign route has significant implications for
drug design in general (23). Finally, the relative role of
these quinoids in vivo is at present unknown; how-
ever, this pathway may occur for a wide range of
synthetic and naturally occurring aromatic ethers and
catechols.
Ack n ow led gm en t. This research was supported by
NSERC Grant WFA0122931, NIH Grant ES06216, and
the University of Illinois at Chicago. We thank Ms.
Vesna Vukomanovic for exceptional technical assistance
and Dr. Manickam Sugumaran, University of Mas-
sachusetts at Boston, for helpful discussion.
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