Cycloastragenol: pharmacokinetics, activities and side effects

General Description

Cycloastragenol, a compound with efficient absorption through the intestinal epithelium, undergoes significant first-pass hepatic metabolism, which may limit its oral bioavailability. It activates telomerase, demonstrating potential in telomere lengthening and DNA damage reduction. Additionally, it exhibits various pharmacological activities such as enhancing skin fitness, regulating lipid metabolism, and displaying antioxidative and anti-inflammatory effects. Studies suggest its relative safety within certain dose ranges, but potential herb-drug interactions and its impact on tumor development warrant further investigation. Overall, Cycloastragenol shows promise for diverse health applications, but comprehensive understanding of its adverse reactions is essential for rational use.

Figure 1. Cycloastragenol

Pharmacokinetics

Cycloastragenol demonstrates efficient absorption through the intestinal epithelium via passive diffusion, as evidenced by a study utilizing in vitro models of human small intestinal mucosa and liver microsomes. However, the presence of metabolites in both the apical and basolateral sides of intestinal cell monolayers suggests potential first-pass intestinal metabolism of Cycloastragenol. Subsequent investigations revealed significant metabolism of Cycloastragenol in rat (17.4%) and human (8.2%) liver microsomes, with lower metabolic capacity observed in other rat tissues compared to the liver. Moreover, administration of Cycloastragenol via continuous gavage led to a notable inhibitory effect on the cytochrome P450 3A4 (CYP3A4) subunit, along with considerable induction of the CYP2E1 subunit. These findings collectively indicate that while Cycloastragenol is efficiently absorbed through the intestinal epithelium, its oral bioavailability may be constrained by extensive first-pass hepatic metabolism. ¹

Activities

Cycloastragenol is a compound that exhibits diverse pharmacological activities. It activates telomerase, which leads to the lengthening of telomeres and a decrease in DNA damage. Cycloastragenol has been shown to increase TERT expression and rescue short telomeres in mice, as well as enhance telomerase activity in T lymphocytes, contributing to enhanced antiviral potential. In addition to telomerase activation, Cycloastragenol also improves skin fitness, wound healing, and fur recovery in elderly mice. It stimulates telomerase activity in human keratinocytes, aiding in wound healing. Cycloastragenol plays a role in regulating lipid metabolism by reducing cytoplasmic lipid droplets in adipocytes and preventing their differentiation. It also stimulates calcium influx in preadipocytes, helping to maintain a balance in lipid metabolism. Furthermore, Cycloastragenol exhibits antioxidative effects by up-regulating total antioxidant capacity and superoxide dismutase activity while down-regulating malondialdehyde. This enhances antioxidant capacity and protects telomeres from oxidative stress. Lastly, Cycloastragenol demonstrates anti-inflammatory properties by suppressing ROS generation, inflammasome activation, mitochondrial cell death, and apoptosis in endothelial cells. It also enhances AMPK phosphorylation, indicating potential anti-inflammatory effects. Overall, Cycloastragenol shows promise as a compound with multifaceted pharmacological effects, making it suitable for various health applications. ²

Side effects

Cycloastragenol has been found to be relatively safe within a certain dose range, with no serious adverse reactions reported. Studies in rats and mice did not show treatment-related mortalities or adverse effects, and no toxic or genotoxic effects were observed in various assays. Additionally, a commercial health maintenance program that included Cycloastragenol as a dietary supplement reported no adverse events over a 5-year period. However, it is important to note that telomerase activation, which is a key effect of Cycloastragenol, has been observed in more than 80% of human tumors, indicating its potential role in tumor development. While administration of Cycloastragenol in mice did not increase the incidence of cancer, it was found to competitively inhibit UDP-glucuronosyltransferase (UGT) 1A8 and noncompetitively inhibit UGT2B7. This suggests the possibility of herb-drug interactions between Cycloastragenol and drugs metabolized by these enzymes when Cycloastragenol reaches certain plasma concentrations. Although an independent expert panel of the Food and Drug Administration (FDA) determined Cycloastragenol to be generally recognized as safe (GRAS) and it has been used as a medical food, further studies on the potential adverse reactions of Cycloastragenol are necessary to fully understand its rational use, especially considering its impact on telomerase and its potential role in tumor development. ³

Reference

1. Zhu J, Lee S, Ho MK, Hu Y, Pang H, Ip FC, Chin AC, Harley CB, Ip NY, Wong YH. In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol, a potent small molecule telomerase activator. Drug Metab Pharmacokinet. 2010;25(5):477-486.

2. Yu Y, Zhou L, Yang Y, Liu Y. Cycloastragenol: An exciting novel candidate for age-associated diseases. Exp Ther Med. 2018 Sep;16(3):2175-2182.

3. Ran R, Zhang C, Li R, Chen B, Zhang W, Zhao Z, Fu Z, Du Z, Du X, Yang X, Fang Z. Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms. Molecules. 2016 Nov 29;21(12):1616.

You may like