PMC

Examples of one- and two-step quinone formation: the formation of a quinone by metabolic oxidation. The quinone (indicated by red ovals) metabolites of acetaminophen and lumiracoxib cause hepatotoxicity due to the formation of a hapten complex with off-target proteins that triggers toxic immune responses.^,, Acetaminophen’s conversion to the reactive quinone N-acetyl-p-benzoquinone imine (NAPQI) illustrates one-step quinone formation, and lumiracoxib’s conversion to lumiracoxib quinone-imine via the intermediate 4′-hydroxylumiracoxib demonstrates two-step quinone formation.^,, The quinone formation model encompasses both one- and two-step quinone formation.

Multiple routes for the oxidative transformation of 3,4-dihydroxyphenylacetic acid. 3,4-Dihydroxyphenylacetic acid (1) is readily oxidized by tyrosinase to its quinone (2). This quinone exhibits three different reactions. It can undergo decarboxylation to the quinone methide (12), which reacts with water producing 3,4-dihydroxybenylalcohol (13). 3,4-dihydroxybenylalcohol is also oxidized by tyrosinase to its quinone (14) and nonenzymatically converted to 3,4-dihydroxybenzaldehyde (11) through quinone methide intermediate (10). Carboxymethyl-o-quinone (2) also isomerizes to quinone methide (7), which generates 3,4-dihydroxymandelic acid (8) by 1,6-addtion of water. Tyrosinase catalyzed oxidation of 3,4-dihydroxy mandelic acid produces the mandeloquinone (9), that is nonenzymatically decarboxylated to the same quinone methide (10) produced by 3,4-dihydroxybenzyl alcohol, thus yielding the same final product, 3,4-dihydroxy benzaldehyde (11). Finally, quinone (2) undergoes rapid intramolecular cyclization to form 2,5,6-trihydroxy benzofuran (4) via furanone (3). This furan is initially believed to form the quinone (5) before getting converted to quinone methide (6), and eventual polymerization.

(A) Projection of complex I dynamics with and without CDL along the bending (PC1) and twisting (PC2) modes sorted by the quinone (Q) position along the tunnel. The quinone position is determined by the distance between the quinone headgroup and Tyr⁸⁷. The quinone motion along the cavity is coupled to the complex I motion along the bending and twisting modes. (B) Quinone binding sites and channels connecting the quinone cavity with the N-side of the membrane. The upper binding sites (d ~ 0.6 to 0.8 nm from Tyr⁸⁷) are shown as green and blue circles, the kink region is marked at d ~ 2.0 nm, and the lower binding sites (d ~ 3.2 to 4.0 nm) are shown as a yellow oval. Channel 1 (blue) is located near the Nqo7 loop region, and channel 2 (in red) is located at the interface between Nqo8 and Nqo9. Both channels are more stable in simulations with CDL and when quinone is bound at the upper site (d ~ 0.6 to 0.8 nm) (see also movie S2). Inset: Distance between Tyr⁸⁷ and the kink region and different quinone binding sites. (C) Schematic representation of structural changes in complex I that couple to the quinone motion. (D) Probability of finding open cavities connected to the quinone binding site.

WB and ELISA were used to test the levels of GLP-1 in LC group, LC + tocopheryl quinone group, HFCC group and HFCC + tocopheryl quinone group (n = 3; *p value < 0.05 vs. LC group; ^#p value < 0.05 vs. HFCC group). (A) Tissue levels of GLP-1 in the four groups were detected by WB. The treatment with tocopheryl quinone increased the expression of GLP-1 in the HFCC group; (B) Plasma levels of GLP-1 in the four groups were detected by ELISA. The treatment with tocopheryl quinone increased the expression of GLP-1 in the HFCC group; (C) Tissue activity of GLP-1 in the four groups was detected by ELISA. The treatment with tocopheryl quinone increased GLP-1 activity in the HFCC group; (D) Tissue IL-6 activity in the four groups was detected by ELISA. The treatment with tocopheryl quinone decreased IL-6 activity in the HFCC group; (E) Tissue TNF-α expression in the four groups was detected by ELISA. The treatment with tocopheryl quinone suppressed the expression of TNF-α in the HFCC group; (F) The expression of endotoxins in the HFCC group was reduced by the treatment with tocopheryl quinone.