ABSTRACT:Gastric absorption of feruloylquinic acid and di-O-caffeoylquinic acid analogs has never been investigated despite their potential contribution to the proposed beneficial health effects leading to reduced risk of type 2 diabetes. Using a cultured gastric epithelial model, with an acidic apical pH, the relative permeability coefficients (P app ) and metabolic fate of a series of chlorogenic acids (CGAs) were investigated. Mechanistic studies were performed in the apical to basal direction and demonstrated differential rates of absorption for different CGA subgroups. For the first time, we show intact absorption of feruloylquinic acids and caffeoylquinic acid lactones across the gastric epithelium (P app ϳ 0.2 cm/s). Transport seemed to be mainly by passive diffusion, because good linearity was observed over the incubation period and test concentrations, and we speculate that a potential carrier-mediated component may be involved in uptake of certain 4-acyl CGA isomers. In contrast, absorption of intact di-O-caffeoylquinic acids was rapid (P app ϳ 2-10 cm/s) but nonlinear with respect to time and concentration dependence, which was potentially limited by interaction with an efflux transporter and/or pH gradient dependence. For the first time, methylation is shown in gastric mucosa. Furthermore, isoferulic acid, dimethoxycinnamic acid, and ferulic acid were identified as novel gastric metabolites of CGA biotransformation. We propose that the stomach is the first location for the release of hydroxycinnamic acids, which could explain their early detection after coffee consumption.
Previous studies have indicated that secondary plant metabolites may modulate glucose absorption in the small intestine. We have characterized a polyphenol-rich herbal extract and its potential intestinal metabolites by LC-MS(2) and investigated the inhibition of glucose transporters SGLT1 and GLUT2 using the well-characterized Caco-2 intestinal model. Differentiated Caco-2 monolayers were incubated with an extract of a mixture of herbs and spices. Glucose transport under sodium-dependent and sodium-free conditions was determined by radiochemical detection of D-[U-(14) C]-glucose. A 54% decrease in transport was observed compared to control. Using sodium-dependent and sodium-free conditions, we demonstrate that the inhibition of GLUT2 was greater than SGLT1. Glycosidase and esterase enzymatic hydrolysis was used to assess the impact of metabolism on the efficacy of inhibition. Glucose transport across the membrane was reduced by 70% compared to the control and was associated with significant increases in flavonoid aglycones, caffeic acid, and p-coumaric acid. These results suggest that intact and hydrolyzed polyphenols, likely to be found in the lumen after ingestion of the supplement, play an important role in the attenuation of glucose absorption and may have potentially beneficial antiglycemic effects in the body.
Scope
This study reports the 24 h human plasma pharmacokinetics of 3,4‐dimethoxycinnamic acid (dimethoxycinnamic acid) after consumption of coffee, and the membrane transport characteristics of certain dimethoxycinnamic acid derivatives, as present in coffee.
Methods and results
Eight healthy human volunteers consumed a low‐polyphenol diet for 24 h before drinking 400 mL of commercially available coffee. Plasma samples were collected over 24 h and analyzed by HPLC‐MS2. Investigation of the mechanism of absorption and metabolism was performed using an intestinal Caco‐2 cell model. For the first time, we show that dimethoxycinnamic acid appears in plasma as the free aglycone. The time to reach the Cmax value of approximately 0.5 μM was rapid, Tmax = 30 min, and showed an additional peak at 2–4 h for several subjects. In contrast, smaller amounts of dimethoxy‐dihydrocinnamic acid (Cmax ∼ 0.1 μM) peaked between 8 and 12 h after coffee intake. In the cell model, dimethoxycinnamic acid was preferentially transported in the free form by passive diffusion, and a small amount of dimethoxycinnamoylquinic acid hydrolysis was observed.
Conclusion
These findings show that dimethoxycinnamic acid, previously identified in plasma after coffee consumption, was rapidly absorbed in the free form most likely by passive diffusion in the upper gastrointestinal tract.
ABSTRACT:There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.
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