NTP technical report on the toxicity studies of a gum guggul extract formulation administered by gavage to Sprague Dawley (Hsd:Sprague Dawley(r) sD(r)) rats and B6C3F1/N mice
Gum guggul extracts (GGEs) are botanical preparations derived from the oleoresin of the Commiphora mukul tree. The preparations are traditionally used in Ayurvedic medicine to treat hyperlipidemia, obesity, diabetes, atherosclerosis, and inflammatory conditions such as arthritis. In the United State...
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| Format: | eBook |
| Language: | English |
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Research Triangle Park, North Carolina, USA
National Toxicology Program, Public Health Service, U.S. Department of Health and Human Services
2020, June 2020
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| Series: | NTP TOX
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| Online Access: | |
| Collection: | National Center for Biotechnology Information - Collection details see MPG.ReNa |
| Summary: | Gum guggul extracts (GGEs) are botanical preparations derived from the oleoresin of the Commiphora mukul tree. The preparations are traditionally used in Ayurvedic medicine to treat hyperlipidemia, obesity, diabetes, atherosclerosis, and inflammatory conditions such as arthritis. In the United States, GGEs are marketed as dietary supplements. GGE toxicity was evaluated due to widespread human exposure through increasing dietary supplement use, demonstrated metabolic and hormone-altering effects, and a lack of available information to adequately assess safe use in humans. Male and female Sprague Dawley (Hsd:Sprague Dawley(r) SD(r)) rats and B6C3F1/N mice were administered a GGE formulation in corn oil by gavage for 28\sdays or 3\smonths. Oral gavage was chosen as the route of exposure for these studies because human exposure primarily occurs by ingestion of encapsulated GGE supplements. Male and female rats displayed significantly increased absolute and relative liver weights relative to the GGE formulation dose administered. Additionally, increased hepatic CYP3A and CYP2B activity was observed in both test species, and metabolic potential was altered in human in vitro assays, suggesting an increased potential for dietary supplement-drug pharmacokinetic interactions Additionally, treatment decreased taurocholate uptake in a human Na+\staurocholate cotransporting polypeptide activity assay and heightened ATPase activity by human P-glycoprotein. Taken together, these data suggest that GGE constituents may act as substrates or cofactors that modify the activity of human metabolic enzymes and transporters. Under the conditions of the 3-month gavage studies, administration of the selected GGE formulation resulted in increased globulin concentrations and decreased bile acid, cholesterol, and phospholipid concentrations in rats, whereas increases in cholesterol and phospholipid concentrations were observed in mice. Decreased mean number of homogenization-resistant spermatids was evident in mice administered the GGE formulation, suggesting the testes might be a target organ of GGE toxicity (lowest-observed-effect level [LOEL]\s=\s62.5\smg/kg/day). Groups of 10\smale and 10\sfemale rats were administered 0, 62.5, 125, 250, 500, or 1,000\smg GGE formulation/kg body weight/day in corn oil by gavage, 5\sdays per week for 3\smonths. Additional groups of 10\smale and 10\sfemale rats were administered the same doses for an interim 28-day study. All rats survived to the end of the study with the exception of three female rats, with a single death occurring in each of the 0, 125, and 500\smg/kg/day groups. Terminal mean body weights of all dosed groups of rats for both the 28-day and 3-month studies were within 5% of vehicle controls. No treatment-related clinical findings were observed. Dose-related increases in absolute and relative liver weights were evident in male and female rats at 28\sdays and 3\smonths. There were no dose-related microscopic findings at 28\sdays or 3\smonths. Increased hepatic CYP2B and CYP3A activities were observed in male and female mice at the highest tested dose, 250\smg/kg/day. The genotoxic potential of the administered GGE formulation was evaluated by quantifying micronucleated reticulocytes or erythrocytes in rat and mouse peripheral blood samples, following 3\smonths of dosing. No apparent increases in the frequency of micronucleated erythrocytes/reticulocytes or changes in the percentage of immature erythrocytes were noted in rats or mice, suggesting that the tested GGE formulation did not induce bone marrow toxicity or alter erythropoiesis in rodents. The potential effects of a GGE formulation on endogenous metabolism were evaluated using human in vitro models. Treatment with a marketed GGE formulation decreased CYP2C9, CYP3A4-mediated testosterone 6β-hydroxylase, and CYP2C19 metabolic activity in human microsomal preparations. No treatment-related effects on organ weights were observed, and there were no dose-related microscopic findings in mice at 28\sdays or 3\smonths. In the 3-month study, elevated serum cholesterol and phospholipid concentrations were noted in female mice. Administration of the tested GGE formulation did not result in significant changes in reproductive organ histopathology of male and female mice. Male mice administered ≥62.5\smg/kg/day exhibited statistically significant lower mean total number of homogenization-resistant spermatids and mean total number of homogenization-resistant spermatids/mg testis relative to the vehicle control group. Mice dosed with 250\smg/kg/day also displayed lower testicular weights (approximately 12%, significant trend) and lower caudal sperm counts relative to vehicle controls, collectively indicating that the GGE formulation examined exhibits the potential to be a male reproductive toxicant. Clinical pathology changes observed at 28\sdays or 3\smonths in male and/or female rats were increased globulin concentration and decreased bile acid, cholesterol, and phospholipid concentrations. Increased hepatic cytochrome P450 (CYP) 2B and CYP3A activities were observed at 28\sdays and 3\smonths in all dosed groups of male and female rats. Groups of 15\smale and 15\sfemale mice were administered 0, 15.5, 31, 62.5, 125, or 250\smg GGE formulation/kg body weight/day in corn oil by gavage, 5\sdays per week for 3\smonths. Additional groups of 10\smale and 10\sfemale mice were administered the same doses for an interim 28-day study. All mice survived to the end of the study. Terminal mean body weights of all dosed groups of mice for both 28-day and 3-month studies were within 7% of vehicle controls. No treatment-related clinical findings were observed. |
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| Physical Description: | 1 PDF file (various pagings) illustrations |