Short Chain (≤C4) Esterification Increases Bioavailability of Rosmarinic Acid and Its Potency to Inhibit Vascular Smooth Muscle Cell Proliferation

Abstract

Rosmarinic acid is a natural phenolic acid and active compound found in many culinary plants, such as rosemary, mint, basil and perilla. Aiming to improve the pharmacokinetic profile of rosmarinic acid and its activity on vascular smooth muscle cell proliferation, we generated a series of rosmarinic acid esters with increasing alkyl chain length ranging from C1 to C12. UHPLC-MS/MS analysis of rat blood samples revealed the highest increase in bioavailability of rosmarinic acid, up to 10.52%, after oral administration of its butyl ester, compared to only 1.57% after rosmarinic acid had been administered in its original form. When added to vascular smooth muscle cells in vitro, all rosmarinic acid esters were taken up, remained esterified and inhibited vascular smooth muscle cell proliferation with IC50 values declining as the length of alkyl chains increased up to C4, with an IC50 of 2.84 µM for rosmarinic acid butyl ester, as evident in a resazurin assay. Vascular smooth muscle cells were arrested in the G0/G1 phase of the cell cycle and the retinoblastoma protein phosphorylation was blocked. Esterification with longer alkyl chains did not improve absorption and resulted in cytotoxicity in in vitro settings. In this study, we proved that esterification with proper length of alkyl chains (C1–C4) is a promising way to improve in vivo bioavailability of rosmarinic acid in rats and in vitro biological activity in rat vascular smooth muscle cells.

Separation and Identification of Antioxidants and Aldose Reductase Inhibitors in Lepechinia meyenii (Walp.) Epling

“…Furthermore, DPPH scavenging assay revealed that the antioxidant potential of rosmarinic acid (DPPH IC50 36.91 µM) was significantly increased after being esterified using short-chain primary Moreover, the present study demonstrated that esterification of rosmarinic acid with short-chain primary alcohols (C 1 -C 4 ) significantly enhanced its antioxidant and AR inhibitory activities (Table 4). A previous study reported that esterification of rosmarinic acid using short to medium chain primary alcohols (C 4 , C 10 , and C 16 ) can increase cell uptake and boost antioxidant activity without significant cytotoxicity [45], whereas a more recent study showed that only short-chain (≤C4) esterification of rosmarinic acid can increase its bioavailability, and esterification with longer alkyl chains leads to severe cytotoxicity [46]. However, no studies have been carried out to compare the antioxidant activity among rosmarinic acid and its short-chain esters (≤C4).…”

Rosmarinic Acid and Related Dietary Supplements: Potential Applications in the Prevention and Treatment of Cancer

“…A study evaluating the bioavailability and nutrient kinetics of Rosmarinus officinalis L. phenolic compounds in healthy humans found that phase II derivatives of RA were RA-glucuronide, methyl-RA-glucuronide, dimethyl-RA-glucuronide, and dimethyl-RA, suggesting absorption in the small intestine [ 13 ]. The absolute oral bioavailability of RA butyl ester was 10.52%, compared to only 1.57% in its original form [ 63 ]. The absolute bioavailability of RA was improved to 89.63 % after pulmonary administration [ 64 ].…”

Influence of Application Forms of Alginite on Phytomass Formation, Bioactive Contents and Antioxidant Activity of Extracts from Plants Rosmarinus officinalis L.

“…It is an ester of caffeic acid and 3,4-dihydroxyphenyl lactic acid. The synthesis is based on two amino acids: L-PHE and L-TYR (Blažević et al, 2021). Rosmarinic acid was the major polyphenol in both of R. officinalis.…”