The Influence of the p-Alkyl Substituent on the Isomerization of o-Quinones to p-Quinone Methides: Potential Bioactivation Mechanism for Catechols

Abstract

Previously, we have shown that an additional bioactivation pathway for the hepatocarcinogen safrole (1-allyl-3,4-(methylenedioxy)benzene) exists which may contribute to its toxic effects: initial O-dealkylation of the methylenedioxy ring, forming the catechol, hydroxychavicol (HC, 1-allyl-3,4-dihydroxybenzene), 2-electron oxidation to the o-quinone (4-allyl-3,5-cyclohexadien-1,2-dione), and isomerization, forming the more electrophilic p-quinone methide (2-hydroxy-4-allylidene-2,5-cyclohexadien-1-one) [Bolton, J. L., Acay, N. M., & Vukomanovic, V. (1994) Chem. Res. Toxicol. 7, 443-450]. In the present investigation, we explored the effects of changing pi-conjugation at the 4-position on both the rate of isomerization of the initially formed o-quinones to the QMs and the reactivity of the quinoids formed from 4-propylcatechol (1), 2,3-dihydroxy-5,6,7,8-tetrahydronaphthalene (2), and 4-cinnamylcatechol (3). We selectively oxidized the catechols to the corresponding o-quinones or p-quinone methides and trapped these reactive electrophiles with glutathione (GSH). The GSH adducts were fully characterized by UV, NMR, and mass spectrometry. Microsomal incubations with the parent catechols in the presence of glutathione produced only o-quinone glutathione conjugates. However, if the trapping agent (GSH) was added after an initial incubation time, both o-quinone and p-quinone methide GSH conjugates were observed. The results indicate that extended pi-conjugation at the para position enhances the rate of isomerization of the o-quinone to the quinone methide. Thus the half-life of the o-quinones decreased in the following order: the o-quinone of 1 > 2 > HC > 3.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

“…The study of the m/z shift as well as the fragmentation pathways observed for the quasi-molecular ions have shown that addition of the base could occur on both the C6 and C9 sites of the steroid B ring in its quinone-methide form. Although compounds attributed to the degradation of an adduct formed by nucleophilic attack of the base on C9 position have already been identified [39,42,43], the corresponding adducts had never been clearly evidenced by LC-MS n until this work. Some complementary work needs now to be developed in order (1) to achieve a complete chromatographic separation of the C6 and C9 adducts which coelute in our LC-MS experiments and (2) to improve the understanding of the particular fragmentation process of this adduct.…”

“…Alternatively, the nucleophilic attack at the C9 position was also proposed for the formation of some estrogen quinone-glutathione adducts, but the occurrence of such species could not be evidenced [39,42]. In this case, the unstable character of such adducts was also reported and only products formed by elimination of glutathione (i.e., 9-dehydro-4OHE and 9-dehydro-2OHE from 4OHE-o-quinone and 2OHE-o-quinone, respectively) were identified as the end products of the degradation of such transient adduct species [39,42]. …”

A Comparison Between Lignans from Creosote Bush and Flaxseed and Their Potential to Inhibit Cytochrome P450 Enzyme Activity

“…These findings are not unexpected as the literature suggests ortho-quinones do not usually undergo adduct formation with cellular macromolecules, instead their damage is usually mediated through an increase in oxidative stress (Chichirau et al, 2005;O'Brien 1991;Monks et al, 1992). Although ortho-quinones may isomerize to para-quinone methides in vivo, a quinone derivative known to form covalent adducts with cellular macromolecules (Powis 1987), this process is unlikely to occur as NDGA is substituted at the benzylic carbon, which severely hinders the isomerization process (Iverson et al, 1995).…”

“…Structural features of the lignans suggest their potential for oxidation to quinone derivatives, a class of compounds known to be electrophilic reactive intermediates (Bolton et al, 1994;Iverson et al, 1995). Since SDG is unlikely absorbed due to the polar nature of the glycosidic groups, it was not investigated for their potential to undergo hepatic P450-mediated bioactivation to a reactive intermediate.…”

Studies of para-quinomethane formation during the tyrosinase-catalyzed oxidation of 4-alkylcatechols

“…These results are entirely in accord with earlier studies by Bolton and co-workers who trapped para-quinomethanes as their glutathione adducts and showed that the ortho-quinone rearrangement is base catalyzed. 22,23 The different .…”