Atherosclerosis 162 (2002) 111 – 117 Inhibitory effect of a novel water-soluble vitamin E derivative on atherosclerosis in rabbits Norimasa Yoshida a, *, Hironobu Murase b , Tsutomu Kunieda b , Shinya Toyokuni c , Tomoyuki Tanaka c , Junji Terao d , Yuji Naito a , Toru Tanigawa a , Toshikazu Yoshikawa a a First Department of Internal Medicine, Kyoto Prefectural Uniersity of Medicine, Kawaramachi -Hirokoji, Kamigyo -ku, Kyoto 602 -8566, Japan b CCI Corporation, Seki, Gifu 501 -3923, Japan c Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto Uniersity, Sakyo -ku, Kyoto, Japan d Department of Nutrition, School of Medicine, The Uniersity of Tokushima, Tokushima 770 -8503, Japan Received 13 March 2001; received in revised form 15 August 2001; accepted 15 August 2001 Abstract A novel vitamin E derivative that is freely soluble in water, 2-(-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), was evaluated for ability to inhibit development of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits or cholesterol-loaded New Zealand White rabbits. Although TMG rapidly entered the circulation blood after oral administration, the blood TMG concentration remained low, while neither TMG nor its metabolites appeared in the low-density lipoprotein (LDL) fraction. TMG did not decrease serum total cholesterol and the various lipoprotein-associated cholesterol fractions (very LDL-, or high-density lipoprotein- (HDL) cholesterol). TMG reduced the serum concentration of thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation) in cholesterol-loaded rabbits but not WHHL rabbits. Nonetheless, TMG inhibited aortic atherosclerosis as effectively as probucol in both models. Our results indicate that TMG opposes progression of atherosclerosis not only by preventing oxidation of LDL, but also by presently unknown mechanisms. Even an antioxidant with no uptake by LDL apparently can inhibit development of atherosclerosis despite a very low serum concentration. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Water-soluble vitamin E derivative; Antioxidant; Watanabe heritable hyperlipidemic (WHHL) rabbit; Cholesterol- loaded rabbit www.elsevier.com/locate/atherosclerosis 1. Introduction As the relationship between oxidative degradation of low-density lipoprotein (LDL) and the progression of atherosclerosis has become more fully understood [1,2], extensive studies have been conducted to determine whether atherosclerosis might be inhibited by adminis- tration of antioxidants. Some clinical studies have demonstrated a benefit from vitamin E, a well-known lipid-soluble antioxidant, especially for controlling heart disease [3,4]. However, recent clinical intervention trials using adequate doses of vitamin E revealed no effect on a composite end- point of cardiovascular complications [5]. In addition, large-scale human secondary prevention studies, namely GCN Hope clearly have not shown any benefit with vitamin E in protecting against recurrence of coronary heart diseases in humans [6]. On the other hand, a few studies have shown that vitamin E is effective in an animal model of atherogenesis [7,8]. Taken together, it is inconclusive whether vitamin E can protect against atherosclerosis [9]. Probucol, another representative lipid-soluble antioxidant, has been reported to show good efficacy in an animal model [10,11], but this agent may decrease high-density lipoprotein (HDL) concen- trations [12]; the latter action could augment the risk of atherosclerosis [13]. Further, probucol at a low-dose did * Corresponding author. Tel.: +81-75-251-5505; fax: +81-75-252- 3721. E-mail address: nyoshida@koto.kpu-m.ac.jp (N. Yoshida). 0021-9150/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0021-9150(01)00702-X