Pergamon Free Radical Biology & Medicine, Vol. 19, No. 2, pp. 197-207, 1995 Copyright © 1995 Elsevier Science Ltd Printed in the USA. All rights reserved 0891-5849/95 $9.50 + .00 0891-5849(95)00010-0 Original Contribution IS a-TOCOPHEROL A RESERVOIR FOR oz-TOCOPHERYL HYDROQUINONE? INDRA KOHAR,* MANUEL BACA, l- CACANG SUARNA, ~t ROLAND STOCKER, ~ and PETER T. SOUTHWELL-KEELY* *Depamnent of Organic Chemistry, The University of New South Wales, Sydney, Australia; t Research Institute of the Scripps Clinic, La Jolla, CA, USA; and * The Heart Research Institute, Camperdown, N.S.W, Australia (Received 26 October 1993; Revised 10 August 1994; Re-revised 22 November 1994; Accepted 19 December 1994) Abstract--The products of oxidation of the a-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-l,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 a-tocopherol (TH) would be a-tocopberyl 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, TQHz, and UQHz) at pH 7.3 by NADH plus FAD. Whole blood reduced PQ rapidly at 37°C to PQH2 but did not reduce TQ to TQHz. Human peripheral blood mononuclear cells took up TQ from a bovine serum albumin complex and reduced it to TQHz. Ingestion of TQ (350 mg) by one of us (PSK) resulted in the formation of TQHz 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. Keywords--Free radicals, a-Toeopherol, c~-Toeopheryl, Hydroquinone, Oxidation INTRODUCTION c~-Tocopherol (TH in Scheme 1) has long been recog- nised as a chain breaking antioxidant in vitro ~ and is believed to function in the same way in vivo, although it may have other properties as well. Thus, radicals (L.), generated from unsaturated fats (LH) in a variety of ways, may react with oxygen to form lipid peroxyl radicals (LOO., eqn 1). LOO. may then react with LH to form lipid hydroperoxides (LOOH) and regenerate L. (eqn 2), thus leading to a propagation of the process. If TH is present, it may compete with LH for peroxyl radicals (eqn 3). L" + 02 ~ LOO" (1) LOO" + LH--, LOOH + L" (2) LOO" + TH ~ LOOH + T" (3) Address correspondence to: Peter T. Southwell-Keely, Department of Organic Chemistry, The University of New South Wales, Sydney 2052, Australia. 197 Several reasons have been advanced for the efficiency of TH as an antioxidant. The first is that the rate of reaction (3) is much faster than that of reaction (2). 2 Second, the a-tocopherol radical (T. in Scheme 1), which is produced in reaction (3), is resonance-stabi- lised and has little tendency to initiate further chains. 2 Third, it has been shown that T. can be reduced back to TH by ascorbic acid. 3'4 Thus, TH is believed to function through a one electron redox cycle involving itself and its radical, T.. A fiartt~r possible explanation for the extraordinary efficiency of TH as an antioxidant has been advanced recendy,s A number of the two and four electron oxidation products of TH and of its model compound, 2,2,5,7,8- pentamethyl-6-chromanol 0PH in Scheme 1) have very good antioxidant activity in their own right s Thus, if TH is oxidised beyond its radical To, its antioxidant activity is not necessarily lost. TIt has been considered to be the major antioxidant protecting cell membranes) However, it has been demonstrated that ubiquinol-10 (UQHz) is an effective lipid-soluble antioxidant 6"7 and a much better pro- tective agent for low density lipoprotein (LDL) than is TH s alone. The high antioxidant activity of UQH2, at least