In vitrobiotransformation of flavonoids by rat liver microsomes

Abstract

1. Sixteen naturally occurring flavonoids were investigated as substrates for cytochrome P450 in uninduced and Aroclor 1254-induced rat liver microsomes. Naringenin, hesperetin, chrysin, apigenin, tangeretin, kaempferol, galangin and tamarixetin were all metabolized extensively by induced rat liver microsomes but only to a minor extent by uninduced microsomes. No metabolites were detected from eriodictyol, taxifolin, luteolin, quercetin, myricetin, fisetin, morin or isorhamnetin. 2. The identity of the metabolites was elucidated using lc-ms and 1H-nmr, and was consistent with a general metabolic pathway leading to the corresponding 3',4'-dihydroxylated flavonoids either by hydroxylation or demethylation. Structural requirements for microsomal hydroxylation appeared to be a single or no hydroxy group on the B-ring of the flavan nucleus. The presence of two or more hydroxy groups on the B-ring seemed to prevent further hydroxylation. The results indicate that demethylation only occurs in the B-ring when the methoxy group is positioned at C4', and not at the C3'-position. 3. The CYP1A isozymes were found to be the main enzymes involved in flavonoid hydroxylation, whereas other cytochrome P450 isozymes seem to be involved in flavonoid demethylation.

Oxidation of the Flavonoids Galangin and Kaempferide by Human Liver Microsomes and CYP1A1, CYP1A2, and CYP2C9

“…It is efficiently oxidized by microsomes from Aroclor 1254-induced rats but not from uninduced rats (Nielsen et al, 1998;Galijatovic et al, 1999), suggesting that Aroclor 1254 induces a P450 isoform not normally present in either human or rat liver.…”

“…Much less is known about the oxidative metabolism of the flavonoids, in particular in humans. Studies with liver microsomes from Aroclor 1254-induced rats demonstrate extensive oxidative metabolism of several flavonoids (Duarte Silva et al, 1997a;Nielsen et al, 1998). This oxidation may be mediated by CYP1A1, as supported by subsequent studies (Duarte Silva et al, 1997b;Doostdar et al, 2000).…”

Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans

“…Hydroxylation is an example of phase I cytochrome P450 mono-oxygenase-dependent activities that may be involved in the metabolism of flavonols. Nielsen et al (1998) showed that microsomes prepared from normal and Aroclor-1254-induced rats were capable of hydroxylating certain flavonols and flavones. The requirement for the metabolic activity was that either one or no hydroxyl groups were present on the Bring.…”

In vitro glucuronidation of xanthohumol, a flavonoid in hop and beer, by rat and human liver microsomes

“…Detection was at 370 nm. Samples dissolved in 100 Wl 75% aqueous acetonitrile containing 1% formic acid were analyzed using a slight modi¢cation of the method of Nielsen et al [2]. Metabolites were eluted with acetonitrile and water containing 1% formic acid at a £ow rate of 0.8 ml/min.…”

“…They have been considered inert and non-essential for human health; however, in the last few years it has been shown that £avonoids a¡ect a wide variety of biological systems in mammals, exhibiting antioxidant, anti-in£ammatory, antiviral, antiproliferative, and anticarcinogenic e¡ects [1]. Studies show that several £avonoids can inhibit or activate the cytochrome P450 (CYP) enzyme system in vitro and in vivo [2,3]. Recently in animal studies much attention has been paid to the antioxidant properties and the inhibitory role of £avo-noids in various stages of tumor development.…”