Role of Catechol-O-Methyltransferase in the Disposition of Luteolin in Rats

Abstract

ABSTRACT:Luteolin is mainly metabolized by phase II enzymes in animals and humans with glucuronidation and sulfation as the two known metabolic pathways. Although methylation of luteolin was reported previously, the structure of the methylated metabolites and the enzymes involved in the process have not been clarified. In our study, two methylated metabolites, M1 (chrysoeriol) and M2 (diosmetin), were identified in the urine after intravenous administration of luteolin to rats, and the data suggested that the methylation was mediated by catechol-O-methyltransferase (COMT). When luteolin was coadministered with a specific COMT inhibitor, entacapone, the formation of M1 and M2 was significantly reduced, whereas the plasma concentration of luteolin increased. Methylation of luteolin was also studied in vitro using rat tissue homogenates. The apparent kinetic parameters associated with the formation of M1 and M2 in vitro were estimated, and regioselectivity of methylation of luteolin was observed. In the in vitro experiment, there was a preference for the formation of M2 over M1. In contrast, accumulation of M1 was preferred in vivo in both rat plasma and urine after an intravenous dose of luteolin. In conclusion, COMT played a crucial role in the disposition of luteolin in rats. Our results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor. Therefore, COMT-associated drug-drug interactions need be considered in the future in luteolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitor.

Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations

“…Catechols have been shown to be good substrates for COMT, UDP-glucuronosyltransferases, and sulfotransferases, which can potentially diminish the oxidation pathway to electrophilic quinones (Taskinen et al, 2003;Chen et al, 2011). This phenomenon was observed in the current analysis.…”

Modulation of (–)-Epicatechin Metabolism by Coadministration with Other Polyphenols in Caco-2 Cell Model

“…These findings suggest a higher affinity of the catechol O-methyl-transferases (COMT) for these compounds than (-)-epicatechin. Quercetin and luteolin were previously identified as high-affinity substrates for COMT (Zhu and Liehr, 1996;Chen et al, 2011). Quercetin already showed higher affinity to COMT than catecholestrogens (Zhu and Liehr, 1996), neurotransmitters (Singh et al, 2003), and other flavonoids (Wang et al, 2012).…”

Discovery of lesser known flavones as inhibitors of NF-κB signaling in MDA-MB-231 breast cancer cells—A SAR study

“…diosmetin (4 0 -methyl luteolin, 13) and chrysoeriol (3 0 -methyl luteolin, 12) in rats. 6 We have screened the bioactivities of methylated and lesser known flavonoids for their possible role in the inhibition of nuclear factor-jB (NF-jB) signaling in the invasive breast cancer cell line MDA-MB-231 and related activities. Limited availability of such compounds in nature prompted us to develop diversity-oriented syntheses to generate a library of methylated as well as hydroxylated flavones and flavonols.…”