This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Kitano, M. Articles by Hosoe, K. Search for Related Content PubMed PubMed Citation Articles by Kitano, M. Articles by Hosoe, K. Social Bookmarking                         What's this?

Subchronic Oral Toxicity of Ubiquinol in Rats and Dogs

Life Science Research Laboratories, Kaneka Corporation, Hyogo, Japan

Dai Watanabe

Kannami Laboratory, Bozo Research Center Inc., Shizuoka, Japan

Shigehito Oda

Gotemba Laboratory, Bozo Research Center Inc., Shizuoka, Japan

Hiroshi Kubo
Hideyuki Kishida

Life Science Research Laboratories, Kaneka Corporation, Hyogo, Japan

Kenji Fujii
Mikio Kitahara

Functional Food Ingredients Division, Kaneka Corporation, Osaka, Japan

Kazunori Hosoe

Life Science Research Laboratories, Kaneka Corporation, Hyogo, Japan

Correspondence: Address correspondence to Mitsuaki Kitano, Life Science Research Laboratories, Kaneka Corporation, 1–8 Miyamae-machi, Takasago-cho, Takasago-shi, Hyogo 676-8688, Japan. E-mail:Mitsuaki.Kitano{at}kn.kaneka.co.jp

Ubiquinol is the two-electron reduction product of ubiquinone (coenzyme Q₁₀ or CoQ₁₀) and functions as an antioxidant in both mitochondria and lipid membranes. In humans and most mammals, including dogs, the predominant form of coenzyme Q is coenzyme Q₁₀, whereas the primary form in rodents is coenzyme Q₉ (CoQ₉). Therefore, the subchronic toxicity of ubiquinol was evaluated and compared in Sprague-Dawley rats and beagle dogs. In the initial rat study, males and females were given ubiquinol at doses of 0, 300, 600, or 1200 mg/kg or ubiquinone at 1200 mg/kg by gavage for 13 weeks. This was followed by the second study, where females were given with doses of 75, 150, 200, or 300 mg/kg/day in order to determine a no observed adverse effect level (NOAEL). In the dog study, the test material was administered to males and females at dose levels of 150, 300, and 600 mg/kg, and ubiquinone was included at 600 mg/kg. Clinical observations, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, blood biochemistry, gross findings, organ weights, and histopathological findings were examined. In both species, determination of plasma and liver ubiquinol concentrations, measured as total coenzyme Q₁₀, were performed. There were no deaths or test article–related effects in body weight, food consumption, ophthalmology, urinalysis, or hematology in rats. Histopathological examinations revealed test article–related effects on the liver, spleen, and mesenteric lymph node in female rats but not in male rats. In the liver, fine vacuolation of hepatocytes was observed in the ubiquinol groups at 200 mg/kg and above. These changes were judged to be of no toxicological significance because they were not considered to induce cytotoxic changes. Microgranuloma and focal necrosis with accumulation of macrophages were observed in the ubiquinol groups at 300 mg/kg and above. These findings were accompanied by slight increases in blood chemistry enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]), which was suggestive of either potential hepatotoxicity or a normal physiological response to ubiguinol loading. Microgranuloma, and focal necrosis were judged to be only adverse effects induced by test article based on their incidence and pathological characteristics. These changes observed in liver were thought due to uptake of the administered ubiquinol by the liver as an adaptive response to xenobiotics, and the microgranulomas and focal necrosis were considered the results of excessive uptake of ubiquinol, which exceeded the capacity for adaptive response. Based on these findings the NOAEL in rats was conservatively estimated to be 600 mg/kg/day for males and 200 mg/kg/day for females. In dogs, there were no deaths or ubiquinol-related toxicity findings during the administration period. No test article–related effects were observed in body weight, food consumption, ophthalmology, electrocardiogram, urinalysis, hematology, or blood chemistry. Histopathological examination revealed no effects attributable to administration of ubiquinol or ubiquinone in any organs examined. Based on these findings, a NOAEL for ubiquinol in male and female dogs was estimated to be more than 600 mg/kg/day under the conditions of this study.

Key Words: Coenzyme Q₁₀ • No Observed Adverse Effect Level • Safety • Toxicity • Ubiquinol • Ubiquinone

International Journal of Toxicology, Vol. 27, No. 2, 189-215 (2008)
DOI: 10.1080/10915810801978060


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?