Inhibitory Interactions of Aspalathus linearis (Rooibos) Extracts and Compounds, Aspalathin and Z-2-(β-d-Glucopyranosyloxy)-3-phenylpropenoic Acid, on Cytochromes Metabolizing Hypoglycemic and Hypolipidemic Drugs

Abstract

Rooibos extract, due to its glucose and lipid lowering effects, has potential as a nutraceutical for improvement of metabolic dysfunction. Potential herb-drug interactions as a result of the use of natural products are of increasing concern. Cytochrome P450 enzymes, CYP2C8, CYP2C9, and CYP3A4, are important in the metabolism of hypoglycemic drugs, such as thiazolidinediones (TZDs) and sulfonylureas, and hypocholesterolemic drugs, such as atorvastatin. This study investigated the effects of rooibos extracts, prepared from "unfermented" and "fermented" rooibos plant material and two of the major bioactive compounds, -2-(β-d-glucopyranosyloxy)-3-phenylpropenoic acid (PPAG) and aspalathin (ASP), on Vivid recombinant CYP450 enzymes. Unfermented (GRT) and fermented (FRE) rooibos extracts inhibited the activity of CYP2C8 (7.69 ± 8.85 µg/mL and 8.93 ± 8.88 µg/mL, respectively) and CYP3A4 (31.33 ± 4.69 µg/mL and 51.44 ± 4.31 µg/mL, respectively) based on their respective IC concentrations. Both extracts dose- and time-dependently inhibited CYP2C8 activity, but only time-dependently inhibited CYP2C9. CYP3A4 showed concentration-dependent inhibition by ASP, GRT, and FRE at 25, 50, and 100 µg/mL concentrations. ASP, GRT, and FRE time-dependently inhibited CYP3A4 activity with GRT and FRE showing a more potent time-dependent inhibition, comparable to erythromycin. These findings suggest that herb-drug interactions may occur when nutraceuticals containing rooibos extracts are co-administered with hypoglycemic drugs such as TZDs, sulfonylureas, and dyslipidemic drug, atorvastatin.

Aspalathin Protects the Heart against Hyperglycemia-Induced Oxidative Damage by Up-Regulating Nrf2 Expression

“…Correspondingly, this study showed that even though MET-treated mice presented with moderately reduced FPG levels, it was unable to prevent oxidative stress associated myocardial structural modifications. This result supports current evidence reporting on the increasing number of natural products and medicinal plants being tested in combination with current drugs such as MET for the prevention and treatment of type DM [ 48 , 49 , 50 ]. An interesting finding from our group has shown that ASP has no inhibitory effect on cytochrome P450 enzymes [ 50 ], suggesting that it could be used in combination with glucose lowering agents such as thiazolidinediones or sulfonylureas to alleviate oxidative injury within a diabetic heart.…”

Aspalathin from Rooibos (Aspalathus linearis): A Bioactive C-glucosyl Dihydrochalcone with Potential to Target the Metabolic Syndrome

“…Although these two case studies do not conclusively infer causality, the sparsity of information relating to the potential of rooibosand aspalathin-drug interactions prompted us to investigate their potential interaction with chronic medications such as statins or oral hypoglycaemic drugs. Using an in vitro recombinant CYP450 enzyme assay, both an aspalathin-rich green rooibos extract and aspalathin dose-and time-dependently inhibited CYP3A4, cautioning against the potential of a herb-drug interaction with hypoglycaemic drugs such as sulfonylureas and statins, including atorvastatin [168]. However, these findings still need to be confirmed by in vivo pharmacokinetic and pharmacodynamic studies.…”

Differential Modulation of Gene Expression Encoding Hepatic and Renal Xenobiotic Metabolizing Enzymes by an Aspalathin-Enriched Rooibos Extract and Aspalathin

“…In this regard, specific polyphenol-CYP450 interactions have a significant impact on the efficiency of drug therapies [13]. Studies on rooibos herbal tea extracts indicated that specific herb-drug interactions should be considered [8,10], as rooibos extracts exhibit various beneficial health promoting effects including antioxidant activity, immune responses, anticancer, and more recently antidiabetic and anti-inflammatory effects [4,11,14,15].…”

“…Overexpression of Cyp2e1 and related carcinogen reactions may inadvertently produce reactive oxygen species and, when not regulated properly, could result in negative physiological effects [34]. A recent in vitro study indicated that fermented and unfermented rooibos extracts and aspalathin exhibit specific herb drugs-interactions by inhibiting CYP450s involved in the metabolism of the hypoglycemic and dyslipidemic drugs [10].…”

“…Dietary exposure of rats to a fermented rooibos extract increased the expression of CYP3A4 in the gut accompanied by a significant decrease in the serum concentration of 4-hydroxymidazolam, a drug known to be metabolized by the enzyme [8]. Rooibos flavonoids were shown to modulate steroid hormone levels in vitro by inhibiting key enzymes in the adrenal steroidogenic pathway [9], while rooibos extracts and aspalathin inhibit the activity of cytochrome P450 enzymes involved in the metabolism of hypoglycemic and hypolipidemic drugs [10]. These investigations emphasize the importance to elucidate the potential beneficial and/or adverse effects of polyphenol-enriched extracts of rooibos when utilized as nutraceutical supplements.…”