THE INFLUENCE OF THE P-ALKYL SUBSTITUENT ON THE ISOMERIZATION OF O-QUINONES TO P-QUINONE METHIDES - POTENTIAL BIOACTIVATION MECHANISM FOR CATECHOLS

Previously, we have shown that an additional bioactivation pathway for the hepatocarcinogen safrole (1-allyl-3,4-(methylenedioxy)benzene) ex ists 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-cycl ohexadien-1-one) [Bolton, J. L., Acay, N. M., and Vukomanovic, V. (199 4) Chem. Res. Toxicol. 7, 443-450]. In the present investigation, we e xplored the effects of changing pi-conjugation at the 4-position an bo th 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-tetrahydronaphthal (2), and 4-cinnamylcatech ol (3). We selectively oxidized the catechols to the corresponding o-q uinones or p-quinone methides and trapped these reactive electrophiles with glutathione (GSH). The GSH adducts were fully characterized by U V, NMR, and mass spectrometry. Microsomal incubations with the parent catechols in the presence of glutathione produced only o-quinone gluta thione conjugates. However, if the trapping agent (GSH) was added afte r an initial incubation time, both o-quinone and p-quinone methide GSH conjugates were observed. The results indicate that extended pi-conju gation 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. In support of this, AMI semiempirical calculations also showed the same trend: an increase in stability of the quinone methide relative to the o-quinone with extending pi-conjugation at the 4-position. Finally, k inetic studies showed that the reactivity of the quinone methides with water increases with decreasing pi-conjugation. These data provide fu rther evidence that formation of these electrophilic quinone methides from o-quinones may be a general bioactivation pathway for synthetic a nd naturally occurring 4-alkylcatechols.