Metabolic Profile of 1,5-Dicaffeoylquinic Acid in Rats, an in Vivo and in Vitro Study

Abstract

ABSTRACT:To explore the metabolism of 1,5-dicaffeoylquinic acid (1,5-DCQA) in rats, liquid chromatography-mass spectrometry in parallel to diode-array detection was used for the rapid detection/characterization of the metabolites formed in bile, urine, and plasma of rats following oral administration of 1,5-DCQA (160 mg/kg). The methylation and glucuronidation of 1,5-DCQA occurring in vitro using rat liver and small intestinal microsomes and cytosols were studied in comparison with those occurring in vivo, and the enzymes involved were also determined. In addition, the anti-HIV (human immunodeficiency virus) activity of three important metabolites was preliminarily evaluated in MT-4 cells infected with HIV-1. A total of 22 metabolites in vivo and in vitro were identified, including four isomeric O-mono-methylated metabolites (M8-M11), nine isomeric O-di-methylated metabolites (M3, M6, M22, and M12-M17), four isomeric O-mono-methyl-glucuronidated metabolites (M2 and M19-M21), four isomeric O-di-methyl-glucuronidated metabolites (M1, M4, M5, and M7), and one glucuronidated metabolite (M18).The O-methylation positions of three important metabolites (M8, M9, and M12) were determined (3؆-, 3-, and 3,3؆-) by comparing with synthesized standards. The efficacy experiments showed that M8, M9, and M12 could inhibit HIV replication with IC 50 values of about 25, 25, and 46 M, respectively. These results suggest that O-methylation and glucuronidation are two important metabolic pathways of 1,5-DCQA, that both rat liver and small intestine can catalyze such reactions by catechol-O-methyltransferase and UDP-glucuronosyltransferases, and that the HIV-1 inhibitory activity of M8, M9, and M12 is comparable to or slightly weaker than that of 1,5-DCQA.Dicaffeoylquinic acids (DCQAs) are a class of natural polyphenolic compounds widely distributed in plants, such as fennel (Parejo et al., 2004), mugwort flowering tops (Fraisse et al., 2003), coffee (Moreira et al., 2001), sweetpotato leaf (Yoshimoto et al., 2002), Ilex brevicuspis Reisseck (Filip and Ferraro, 2003), Isertia pittieri (Um et al., 2002), and Eleutherococcus senticosus (Tolonen et al., 2002). Structurally, they are characterized by two caffeic acid molecules connected to one quinic acid molecule through ester bonds. In the past 10 years, DCQAs have been established as an important class of compounds with their potential effects of inhibiting HIV-1 integrase selectively and preventing HIV-1 replication in tissue culture at nontoxic concentrations (McDougall et al., 1998; Robinson et al., 1996a, b;King et al., 1999). HIV-1 integrase is an essential enzyme that mediates integration of the HIV genome into the host chromosomes. Zhu et al. (1999) reported that such inhibition of DCQAs on the HIV-1 integrase is irreversible toward its conserved amino acid residues in the central core domain during catalysis. The combinations of HIV integrase inhibitors with already existing inhibitors for HIV reverse transcriptase and protease have been suggested to be strongly synergetic (Ro...

Isolation and Identification of Phase 1 Metabolites of Demethoxycurcumin in Rats

“…In this study, the major metabolites of demethoxycurcumin in urine were hexahydro-demethoxycurcumins (M-5 and M-6) and the 5-O-methyl-hexahydrodemethoxycurcumins (M-7 and M-8) together with traces of 5-dehydroxy-dihydro-demethoxycurcumins (M-9), whereas the major metabolites in feces were 5-dehydroxy-hexahydro-demethoxycurcumin (M-1 and M-2) and 5-dehydroxy-octahydro-demethoxycurcumin (M-3 and M-4). Combined with previous reports on the metabolism of curcuminoids (Holder et al, 1978;Wahlstrom et al, 1978;Ireson et al, 2001;Hoehle et al, 2006), it may be presumed that some demethoxycurcumin should initially undergo reduction to form dihydro-, tetrahydro-, hexahydro-(M-5 and M-6), and octahydro-demethoxycurcumin in a stepwise fashion (Ireson et al, 2002), followed by dehydroxylation (Feighner et al, 1980;Bokkenheuser et al, 1981;Kasahara et al, 1995) to form 5-dehydroxy-dihydro-(M-9), 5-dehydroxy-hexahydro-(M-1 and M-2), and 5-dehydroxy-octahydro-demethoxycurcumins (M-3 and M-4); on the other hand, some demethoxycurcumin may be initially methylated (Yang et al, 2005), followed by reduction to form 5-O-methyl-hexahydro-demethoxycurcumins (M-7 and M-8). Based on the metabolite profiles, the metabolic pathways of demethoxycurcumin in rats are proposed (Fig.…”

Hyperpigmentation mechanism of methyl 3,5-di-caffeoylquinate through activation of p38 and MITF induction of tyrosinase

“…In addition to inhibition of human immunodeficiency virus-1 integrase and its replication [19][20][21], the antioxidant activities of caffeoylquinic acid derivatives [15,22] were also reported. However, no previous study has examined the activity of methyl 3,5-di-caffeoylquinate (3,5-diCQM) (Fig.…”

Interaction of Bioactive Components Caffeoylquinic Acid Derivatives in Chinese Medicines with Bovine Serum Albumin

“…It is widely accepted that the distribution, free concentration, and metabolism of various compounds can be affected as a result of binding to serum albumins in the blood stream. 18) From a review of the literatures, 14,[19][20][21] it was proposed that caffeic acid, tissular methylated metabolites (e.g. ferulic and isoferulic acids) and hippuric acid were some of the metabolites of CQAs (e.g.…”

“…Most important, CQAs have been established as an important class of compounds with their potential effects of inhibiting human immunodeficiency virus (HIV)-1 integrase selectively and preventing HIV-1 replication in tissue culture at nontoxic concentrations. [12][13][14] Structure-activity relationship studies showed that their antioxidant, 5) antitumor, 6) hepatoprotective 7) and antimutagenicity 11) activities increased in proportion to the number of caffeoyl groups. Recently, it was also concluded that the radical scavenging activity of natural dicaffeoylquinic acids in the biological aqueous system might depend on the positions of caffeoyl ester groups.…”