Preclinical studies on safety of fullerene upon acute oral administration and evaluation for no mutagenesis
Introduction
Despite a wide range of attempts on the biological potency of fullerenes, less is known about the toxicity in mammals. Fullerene arranging the 60 carbon atoms with 30 carbon–carbon (C–C) double bonds and 60 C–C single bonds as shown in Fig. 1 was discovered in 1985 (Kroto et al., 1985). Intense interest has been focused on this unique molecule having spherical symmetry in the last two decades for the characterization with chemical and biological properties of fullerene (Krusic et al., 1991, Arbogaast et al., 1991, McEwen et al., 1992). Various water-soluble fullerenes were prepared by the use of chemical modification of hydrophobic fullerene to widely explore biological activities. It is reported that several water-soluble fullerenes indicated low cytotoxicity while displaying their biological efficacy both in vitro (Tsuchiya et al., 1995, Baierl et al., 1996, Dugan et al., 1997) and in vivo (Yamago et al., 1995, Dugan et al., 1996, Satoh et al., 1997). Fullerene was recognized as a free radical scavenger and water-soluble fullerenes were proved to reduce the level of intracellular peroxidation (Xiao et al., 2005). Attempts for pharmaceutical technologies with a series of water-soluble fullerenes have been explored for their potential as anti-HIV (Schinazi et al., 1993, Toniolo et al., 1994, Rajagopalan et al., 1996) and anticancer (Chiang et al., 1995, Miyata and Yamakoshi, 1997) agents. Quite recently, Moussa have reported that pristine C60 is a powerful liver-protective agent against free-radical-mediated liver injury (Gharbi et al., 2005).
For the promising pharmacotherapeutic application, sufficient data regarding in vitro and in vivo toxicological studies of fullerenes should be accumulated. Thus, we focused our attention on the mixture of C60 and C70, a more practical industrial composition of fullerenes (or fullerite), and we have designed a protocol to determine the acute oral median lethal dose and to investigate the acute toxicity of fullerenes.
Section snippets
A single dose oral toxicity study of fullerenes in rats
Fullerenes (the mixture of C60 and C70, fullerite), sublimed technical grade, purity: 99.5%, were supplied from Vitamin C60 BioResearch Corp. (Tokyo, Japan).
Acute toxicity
Compound-colored stools and mean body weights in Sprague–Dawley rats for the duration from 1- to 15-day after administration at the level of 2000 mg/kg of fullerenes were measured (Fig. 2(A) and (B)). As for absolute body weights of the 2000 mg/kg, there were no differences as compared with the control group (0 mg/kg). Compound-colored stool was found at 6 h after administration in four males and one female of the 2000 mg/kg group, as well as in one male of the 2000 mg/kg group on day 2. No changes
Discussion
Fullerenes were administered once orally to both sexes at a dose level of 2000 mg/kg. The control group that received a vehicle only was also arranged. During the observation study period, no deaths were recorded in either sex of the control or 2000 mg/kg group. All groups gained weight in a similar pattern with the control group. Administration of fullerenes did not induce abnormalities in the necropsy. In the observation of clinical signs, compound-colored stool was noted on day 1 in both sexes
Acknowledgments
The authors are grateful to Mitsubishi Chemical Safety Institute Ltd., for technical assistance with analysis and metabolism. The mammal treatment, and measurement were completed by Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., Japan (GLP, Standards for Conduct of Non-clinical Studies on the Safety of Drugs, MHW, Ordinance no. 21, March 26, 1997).
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2019, Journal of Molecular LiquidsCitation Excerpt :The use of berberine in combination with fullerene can reverse this effect. The results of latter research suggest that fullerenes water solutions have good membranotropic properties [19], have not mutagenic activity at oral administration [20] and can enhancement of anticancer activity of antitumor antibiotics [9,10,21]. Therefore, the use of fullerene C70 with berberine may increase its oral bioavailability and solve the problems encountered with berberine oral delivery.