In vitro inhibition of human P450 enzymes by prenylated flavonoids from hops, Humulus lupulus

Abstract

1. Several unique flavonoid compounds have recently been isolated from hops, Humulus lupulus, and their presence has been detected in beer. Their chemical structures are similar to other plant-derived compounds, many present in the human diet, that have been shown to have cancer chemopreventive properties due, in part, to inhibition of cytochrome P450 enzymes that activate carcinogens. Additionally, preliminary studies have shown these flavonoids (at 100 microM) to be inhibitory of P450-mediated activation reactions in a variety of in vitro systems. Thus, the in vitro effects of these phytochemicals on cDNA-expressed human CYP1A1, CYP1B1, CYP1A2, CYP3A4 and CYP2E1 were currently examined by the use of diagnostic substrates and the carcinogen AFB1. 2. At 10 microM, the prenylated chalcone, xanthohumol (XN), almost completely inhibited the 7-ethoxyresorufin O-deethylase (EROD) activity of CYP1A1. At the same concentration, other hop flavonoids decreased the EROD activity by 90.8-27.0%. 3. At 10 microM, XN completely eliminated CYP1B1 EROD activity, whereas the other hop flavonoids showed varying degrees of inhibitory action ranging from 99.3 to 1.8%. 4. In contrast, the most effective inhibitors of CYP1A2 acetanilide 4-hydroxylase activity were the two prenylated flavonoids, 8-prenylnaringenin (8PN) and isoxanthohumol (IX), which produced > 90% inhibition when added at concentrations of 10 microM. 5. CYP1A2 metabolism of the carcinogen AFB1 was also inhibited by IX and 8PN as shown by decreased appearance of dihydrodiols and AFM1 as analysed by hplc. IX and 8PN also decreased covalent binding of radiolabelled AFB1 to microsomal protein in a concomitant manner. 6. XN, IX and 8PN, however, were poor inhibitors of CYP2E1 and CYP3A4 as measured by their effect on chorzoxazone hydroxylase and nifedipine oxidase activities respectively. 7. These results suggest that the hop flavonoids are potent and selective inhibitors of human cytochrome P450 and warrant further in vivo investigations.

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

“…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.…”

Optimization of conditions for supercritical fluid extraction of flavonoids from hops (Humulus lupulusL.)

“…Xanthohumol and other prenylated chalcones are now attracting greater attention in the medical field. To date, some prenylflavonoids examined in vitro present many biological activities: inhibition of the growth of breast cancer (MCF-7) cells in a dose-dependent manner (Miranda et al, 1999); inhibition of the cytochrome P450-mediated activation of procarcinogens (Henderson et al, 1998); inducing the activity of the carcinogen-detoxifying enzyme, quinone reductase (Miranda et al, 2000). Other biological activities include inhibition of bone resorption, inhibition of diacylglycerol acyltransferase and antimicrobial activities (Tobe et al, 1997;Tabata et al, 1997;Mizobuchi and Sato, 1984).…”

Anti-Invasive and Anti-Angiogenic Effects of Xanthohumol and Its Synthetic Derivatives

“…Compound 3, also known as dehydrocycloxanthohumol, is a pyranochalcone that has also exhibited a variety of biological activities. Compound 3 possesses anti-fungal, anti-proliferative, antimutagenic and antioxidative activities (Miranda et al, 1999;Gerhauser et al, 2002;Henderson et al, 2000;Miranda et al, 2000a;Miranda et al, 2000b;Stevens et al, 2003;Nikolic et al, 2005). Based upon the previous reports, both Compounds 1 and 3 seem to have similar activities against cancer cell behavior in vitro except anti-invasive effect.…”