Safety Assessment of Ubiquinol Acetate: Subchronic Toxicity and Genotoxicity Studies

Abstract

Coenzyme Q10 (CoQ10) is a lipid soluble, endogenous antioxidant present at highest levels in the heart followed by the kidney and liver. The reduced CoQ10 ubiquinol is well known for its chemical instability and low bioavailability. The present study was designed to synthesize ubiquinol acetate, which is more stable and biologically active, and further evaluate its safety and genotoxic potential. Synthesized ubiquinol acetate showed better stability than that of ubiquinol at the end of 3 months. In vitro genotoxicity studies (AMES test, in vitro micronucleus and chromosomal aberration) showed ubiquinol acetate as nongenotoxic with no clastogenic or aneugenic effects at high dose of 5000 and 62.5 μg/mL, respectively. In subchronic toxicity study, ubiquinol acetate was administered orally to Sprague Dawley rats at 150, 300, and 600 mg/kg/day for 90 days. No treatment related adverse effects were observed in males at 600 mg/kg/day; however, females showed treatment related increase in AST and ALT with small focal irregular white-yellow spots in liver on gross necropsy examination. Histopathological evaluation revealed hepatocellular necrosis in high dose females which was considered as adverse. Based on the results, the No-Observed-Adverse-Effect Level (NOAEL) of ubiquinol acetate in males and females was determined as 600 and 300 mg/kg/day, respectively.

Histopathological comparison of the salivary glands’ acini and striated ducts after experimental prolonged daily administration of oral ubiquinone doses in rats

“…The three major salivary glands did not display profound regressive histological changes such as atrophy or degeneration of the parenchyma. This result came in agreement with outcomes of studies conducted by Deshmukh et al [10] and another experiment undertaken in 2011 by Kitano et al [11], except for the finding of a significant increase in diameter (hypertrophy) of serous acini in both parotid and submandibular glands in the current study. This increase in the size of acini (hypertrophy) could be attributed to several causes, such as repeated feeding with certain dietary supplements like grape skin extract or tannic acid [12], where glandular hypertrophy is considered a reversible adaptive response.…”

“…At such a level, female rats were reported to suffer an increase in liver enzymes with gross focal liver changes. Histopathological evaluation of the hepatic areas with focal changes revealed hepatocellular necrosis [10]. Therefore, the daily oral dose of 300 mg/kg CoQ10 was selected.…”

Stability of Reduced and Oxidized Coenzyme Q10 in Finished Products

“…The stability issues associated with CoQ10 are more pronounced with the use of rCoQ10, which is quickly oxidized, when in contact with air or after light exposure [44,47,48]. Providing quality rCoQ10 products is therefore quite demanding in terms of obtaining a stable formulation [28,47].…”

“…The stability issues associated with CoQ10 are more pronounced with the use of rCoQ10, which is quickly oxidized, when in contact with air or after light exposure [44,47,48]. Providing quality rCoQ10 products is therefore quite demanding in terms of obtaining a stable formulation [28,47]. However, the stability of oCoQ10 is also affected by some environmental conditions (UV-light and temperature [48][49][50][51][52]) as well as the presence of reducents in the products [52].…”

Genotoxic risk in humans and acute toxicity in rats of a novel oral high-dose coenzyme Q10 oleogel

“…In most mammals, including humans, CoQ 10 is the predominant form with a ten isoprenyl unit side chain in trans configuration at C6 of the 2,3-dimethoxy-5-methyl-6-decaprenyl-1,4-benzoquinone (ubiquinone) or -1,4-benzoquinol (ubiquinol, the reduced form). It is mostly found in heart, kidney and liver [ 3 ]. CoQ 10 deficiencies can be caused by a primary disorder in its biosynthetic pathway.…”