Is alpha-tocopherol a reservoir for alpha-tocopheryl hydroquinone?

The products of oxidation of the alpha-tocopherol model compound, 2,2,5,7,8-pentamethyl-6-chromanol (PH) by t-butyl hydroperoxide in chloroform varied with the amount of water present. In the presence of a trace of water, the main products were the spirodimer (PSD) and spirotrimer (PST). As the content of water increased, the main product became 2-(3-hydroxy-3-methylbutyl)-3,5,6-trimethyl-1,4-benzoquinone (PQ). Oxidation of PH in aqueous liposome suspension also produced PQ as the major product. These results suggested that, in aqueous solutions, the major oxidation product of PH would be PQ and of alpha-tocopherol (TH) would be alpha-tocopheryl quinone (TQ). The ease of reduction of PQ and TQ was studied in chemical and biological systems. PQ, TQ, and ubiquinone-10 (UQ) were rapidly reduced to their respective hydroquinones (PQH2, TQH2, and UQH2) at pH 7.3 by NADH plus FAD. Whole blood reduced PQ rapidly at 37 degrees C to PQH2 but did not reduce TQ to TQH2. Human peripheral blood mononuclear cells took up TQ from a bovine serum albumin complex and reduced it to TQH2. Ingestion of TQ (350 mg) by one of us (PSK) resulted in the formation of TQH2 during a 5 h period. These results demonstrate that several biological systems are able to reduce TQ to TQH2 and that it is a reaction that may occur normally in vivo.

Antioxidant activity of 5-alkoxymethyl-6-chromanols.

The 5-alkoxymethyl-2,2,7,8-tetramethyl-6-chromanols (II) are excellent antioxidants against autoxidising safflower oil (ASO), although not as good as 2,2,5,7,8-pentamethyl-6-chromanol (I), the model compound of alpha-tocopherol. The aim of this work was to determine whether the rate of reaction of (II) with the radicals diphenylpicrylhydrazyl (DPP*) and galvinoxyl (ArO*) was directly proportional to their antioxidant activity against ASO. Compounds (II) reacted faster with DPP* than with ArO* but, in each case, slower than compound (I). The rates of reaction of I and II with both radicals followed the order I > II (R = H) > II (R = CH3) > II (R = other alkyls) and were directly proportional to their antioxidant activity against ASO.

Cytotoxicity of tocopherols and their quinones in drug-sensitive and multidrug-resistant leukemia cells.

Cytotoxicities of tocopherols (alpha-T, gamma-T, delta-t), their para (alpha-TQ, gamma-TQ, delta-TQ)- and ortho (Tocored)-quinone oxidation products, the synthetic quinone analog of gamma-TQ containing a methyl group substituted for the phytyl side-chain (TMCQ) and the synthetic quinone analog of Tocored containing a methyl group substituted for the phytyl side-chain (PR) were measured in acute lymphoblastic leukemia cell lines that are drug-sensitive (CEM) and multidrug-resistant (CEM/VLB100). Among tocopherols, only delta-T exhibited cytotoxicity. Among para quinones, alpha-TQ showed no cytotoxicity, while gamma-TQ and delta-TQ were highly cytotoxic in both CEM and CEM/VLB100 cell lines (LD50 < 10 muM). delta-TQ and gamma-TQ were more cytotoxic than the widely studied chemotherapeutic agent doxorubicin, which also showed selective cytotoxicity to CEM cells. The orthoquinone Tocored was less cytotoxic than doxorubicin in drug-sensitive cells but more cytotoxic than doxorubicin in multidrug-resistant cells. Cytotoxicity was not a function of the phytyl side-chain since both TMCQ and PR were cytotoxic in leukemia cells. Cytotoxic para and ortho quinones were electrophiles that formed adducts with nucleophilic thiol groups in glutathione and 2-mercaptoethanol. Cytotoxicity was enhanced when the glutathione pool was depleted by preincubation with buthionine-[S,R]-sulfoximine, but cytotoxicity was diminished by the addition of N-acetylcysteine to cultures. alpha-T also diminished the cytotoxicity of para- and orthoquinones. Buthionine-[S,R]-sulfoximine did not block the inhibitory effect of either N-acetylcysteine or alpha-T, showing that these agents did not act solely by maintaining the glutathione pool as an essential antioxidant system. In conclusion, tocopherylquinones represent a new class of alkylating electrophilic quinones that function as highly cytotoxic agents and escape multidrug resistance in acute lymphoblastic leukemia cell lines.