Metabolic Fate of Luteolin in Rats: Its Relationship to Anti-inflammatory Effect

Abstract

Luteolin is a naturally occurring flavone that reportedly has anti-inflammatory effects. Because most luteolin is conjugated following intestinal absorption, free luteolin is likely present at low levels in the body. Therefore, luteolin metabolites are presumably responsible for luteolin bioactivity. Here we confirmed that luteolin glucuronides, especially luteolin-3'-O-glucuronide, are the major metabolites found in plasma after oral administration of luteolin (aglycone) or luteolin glucoside (luteolin-7-O-glucoside) to rats. Luteolin-4'-O-glucuronide and luteolin-7-O-glucuronide were also detectable together with luteolin-3'-O-glucuronide in the liver, kidney, and small intestine. Next, we prepared these luteolin glucuronides and compared the anti-inflammatory effects of luteolin and luteolin glucuronides on gene expression in lipopolysaccharide-treated RAW264.7 cells. Luteolin glucuronides, especially luteolin-7-O-glucuronide, reduced expression of inflammatory genes in the cells, although their effects were weaker than those of luteolin. These results indicate that the active compound responsible for the anti-inflammatory effect of luteolin in vivo would be luteolin glucuronide and/or residual luteolin.

Enhanced antioxidant activity, antibacterial activity and hypoglycemic effect of luteolin by complexation with manganese(ii) and its inhibition kinetics on xanthine oxidase

“…[1][2][3] It has been reported to have anti-inammatory, antioxidative, antidiabetic, antimicrobial and anticancer activities in vivo. [4][5][6][7][8] Luteolin has received increasing attention due to its various biological activities and pharmacological effects and has been widely applied in the elds of medicine and functional foods.…”

The mechanism(s) of action of antioxidants: From scavenging reactive oxygen/nitrogen species to redox signaling and the generation of bioactive secondary metabolites

“…330 ng/mL at 1 hour after administration, suggesting that bioactivities observed in vitro at around 0.1‐1 µM concentrations might have in vivo relevance. As to its metabolic fate, several recent studies addressed the metabolism of luteolin ( 9 ) in cell cultures and/or after oral ingestion in rodents . Luteolin ( 9 ) is absorbed faster in the small than in the large intestine, and undergoes a significant intestinal first‐pass metabolism through conjugation to mono‐ and diglucuronides ( 9a ‐ 9d , 9k ‐ 9m ) by UDP‐glucuronosyltransferases, and, in parallel to this, O ‐methylation by COMT forms chrysoeriol ( 9e ) and diosmetin ( 9 f ) that are then glucuronidated as is the parent compound (chemical structures are presented in Figure A).…”

“…While the main metabolite 9c was inactive at the same concentration, 9a and particularly 9b were found to partially retain the activity of their parent compound, with 9b acting ca. half as strong as luteolin ( 9 ) . Considering the concentrations that can be achieved in vivo , compounds acting weak at 25 µM concentration might seem to have low chance to exert a relevant in vivo activity.…”

“…As to its metabolic fate, several recent studies addressed the metabolism of luteolin (9) in cell cultures and/or after oral ingestion in rodents. [121][122][123] Luteolin (9) is absorbed faster in the small than in the large intestine, and undergoes a significant intestinal first-pass metabolism through conjugation to mono-and diglucuronides (9a-9d, 9k-9m) by UDP-glucuronosyltransferases, 121 and, in parallel to this, O-methylation by COMT forms chrysoeriol (9e) and diosmetin (9 f) that are then glucuronidated as is the parent compound 123 (chemical structures are presented in Figure 5A). Administering a single 20 µM/kg oral dose in rats, tissue distribution of luteolin (9) and its metabolites 9b-9g, 9i and 9j was found to be rapid into the organs, with the exception of 9e and 9j whose presence was not detectable in the brain at any time probably due to the blood-brain barrier.…”

“…half as strong as luteolin (9). 126 Considering the concentrations that can be achieved in vivo, compounds acting weak at 25 µM concentration might seem to have low chance to exert a relevant in vivo activity. However, evidence suggests that a microenvironment-dependent deconjugation can also take place: an unspecified monoglucuronide of 9, most likely 9c, was found to be hydrolyzed to free luteolin by human β-glucuronidase released by neutrophils.…”