Suppression of cyclooxygenase‐2 gene transcription by humulon of beer hop extract studied with reference to glucocorticoid

Abstract

In murine osteoblastic MC3T3-E1 cells which produced prostaglandin E2 as a bone resorption factor, the cyclooxygenase-2 induction by tumor necrosis factor K K (TNFK K) was suppressed by dexamethasone with an IC 50 of 1 nM. Humulon isolated from hop extract for beer brewing was reported previously as an inhibitor of bone resorption [Tobe, H. et al. (1997) Biosci. Biotech. Biochem. 61, 158^159]. We showed that the compound suppressed the TNFK K-dependent cyclooxygenase-2 induction with an IC 50 of as low as about 30 nM as demonstrated experimentally by catalytic activity assay, Northern blot analysis and promoter analysis. Reporter gene experiments suggested that humulon blocked the cyclooxygenase-2 expression mediated by NFU UB and NF-IL6, but the intracellular glucocorticoid receptor was not involved. The catalytic activity of cyclooxygenase-2 was inhibited by humulon with an IC 50 of as high as 1.6 W WM. These results showed that humulon suppressed cyclooxygenase-2 induction at the step of transcription.z 2000 Federation of European Biochemical Societies.

The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties

“…Hop extracts and/or compounds have been reported to be "active" or the equivalent by the authors of the given studies in the following assays: various antioxidant and/or chemoprevention (Gerhäuser et al, 2002;Gerhäuser et al, 2001;Liegeois et al, 2000;Masaki et al, 1995;Oyaizu et al, 1994;Stevens et al, 2002;Tagashira et al, 1995), antimicrobial, particularly against Gram positive bacteria (Grange and Davey, 1990;Langezaal et al, 1992;Matos et al, 2001;Ohsugi et al, 1997;Racz et al, 1980;Simpson and Smith, 1992;Tagashira et al, 1997), and cytotoxicity (Bae et al, 1996;Liu et al, 2001;Miranda et al, 1999;Shipp et al, 1994). Many constituents have been reported from hops (Farnsworth, 2003), among which in addition to the aforementioned estrogenic properties, many have been shown to possess other types of biological activity (Honma et al, 1998;Shipp et al, 1994;Tabata et al, 1998;Tobe et al, 1995;Tobe et al, 1997;Yasukawa et al, 1995) such as potential cancer chemopreventive activity (Gerhäuser et al, 2001a;Miranda et al, 2000a) and suppression of COX-2 gene transcription (Yamamoto et al, 2000). The major chalcone xanthohumol, as well as the flavanones isoxanthohumol, and 6PN and 8PN show various forms of antioxidant activity in vitro in the micromolar range, and are weakly cytotoxic to certain cancer cell lines (Gerhäuser et al, 2001a;Gerhäuser et al, 2001b;Milligan et al, 1999;Miranda et al, 2000a;Miranda et al, 2000b).…”

Isohumulones, Bitter Acids Derived from Hops, Activate Both Peroxisome Proliferator-activated Receptor α and γ and Reduce Insulin Resistance

“…Fibrate drugs, which act as ligands for PPAR␣ and thiazolidinedione drugs, which are ligands for PPAR␥, are often used to treat hyperlipidemia and hyperglycemia, respectively. The combination therapy of these medications is an attractive option for the treatment of obese type 2 diabetics (10,11). Compounds that have dual agonistic activity on both of these receptors have been shown to improve insulin sensitivity and dyslipidemia in obese diabetic animals (6,27).…”

“…Hops, which have been used as an herbal medicine for many years, were shown to contain several compounds that have significant biological effects, such as 8-prenylnaringenin, which has estrogenic activity (37), and xanthohumol and hexahydro-colupulone, which were shown to inhibit the growth of cancers (38). Humulone was also shown to have anti-tumor effects (10,11,39). Isohumulones, which are isomerized humulones, are present in beer.…”

“…␣ acids, derived from hops by isomerization during the brewing process. Humulone was shown to inhibit angiogenesis by suppressing cyclooxygenase-2, one of the key enzymes involved in carcinogenesis (10,11); other than having antibacterial properties, no physiological effects were reported for isohumulones (12).…”

Recent Advances in the Study on Resveratrol

“…42) Vaticanol C, a resveratrol tetramer, activates PPARα and PPARβ/δ in vitro (5 μM) and in vivo (0.04% of diet for 8 weeks), but has no effect on SIRT1 activation. 32) Polyphenolic compounds such as apigenin, chrysin, 43,44) and humulon 45) ( Fig. 1) suppress COX-2 expression and also activate PPARα and/or γ.…”