Cancer Chemopreventive Potential of Humulones and Isohumulones (Hops α- and Iso-α-acids): Induction of NAD(P)H:Quinone Reductase as a Novel Mechanism

Abstract

Phytochemical analysis and chemopreventive testing of a special “α-/β-acid free” hops extract led to the identification of isohumulones (hops iso-α-acids) as potent inducers of NAD(P)H:quinone reductase (QR) activity. CD values (concentrations required to double the specific activity of QR in Hepa1c1c7 cell culture) were in the range of 1.3 to 10.2 μg/mL, with CD value of trans-isohumulone < cis-isoadhumulone < cis-isocohumulone < cis-isohumulone (+ trans-isoadhumulone). Humulones (hops α-acids) were equally active with CD values of 3.4 to 7.6 μg/mL. However, these activities were accompanied by cytotoxicity. Cohumulinone and humulinone, oxidation products of co- and n-humulone, were inactive. We further identified isohumulones as potent inhibitors of lipopolysaccharide-induced inducible nitric oxide synthase (iNOS) activity in Raw264.7 cell culture, with IC50 values of 5.9 – 18.4 μg/mL. Humulones and humulinones were inactive at concentrations < 20 μg/mL. These results indicate that isohumulones, which are considered as the most abundant class of polyphenols in beer, should by further investigated for chemopreventive efficacy in animal models.

Mechanistic Toxicity Assessment of Hexahydroisohumulone in Canine Hepatocytes, Renal Proximal Tubules, Bone Marrow-Derived Mesenchymal Stem Cells, and Enterocyte-like Cells

“…To a lesser degree, an extrahepatic production of ROS/RNS by HEX was observed in CPTC, BMSC and ELC (Figure 1B, 2A and 2B). In contrast to these results in primary canine cells, others reported that other hop components worked as antioxidants in vivo and in vitro [32][33][34][35].…”

“…Isohumulones had antioxidant activity in Dahl salt-sensitive (DS) rats fed a commercial diet containing 8% NaCl and 0.3% isohumulone and in murine RAW 264.7 cells (IC 50 value of 5.9 -18.4 µg/mL) [32,33]. TRA and xanthohumol moderately attenuated the production of peroxyl, singlet oxygen and hydroxyl radicals, and peroxy nitrite/ferric ion derived from a cell-free assay, respectively [34].…”

“…Natural products and phytochemicals with antioxidant activity are utilized to delay and inhibit oxidation; but may also serve as prooxidants like carotenoids and flavonoids [31]. Isohumulones showed antioxidant activity in Dahl salt-sensitive (DS) rats and mouse macrophage RAW 264.7 cells, but TRA served as a poor antioxidant against the highly reactive hydroxyl radical [32][33][34]. Thus, it is not clear whether HEX intake may be beneficial or harmful to general health.…”

Comparative In Vitro Cytotoxicity of 20 Potential Food Ingredients in Canine Liver, Kidney, Bone Marrow-Derived Mesenchymal Stem Cells, and Enterocyte-like Cells

“…28 They can inhibit LPS-induced iNOS activity in RAW 264.7 macrophages at 6-18 lg/ml and induce NAD(P)H:quinone reductase activity at 1-10 lg/ml in murine hepatoma cells with cytotoxicity seen at an LD 50 > 20 lg/ml. 29 Green tea derived from Camelis sinensis consists of 30% polyphenols termed catechins. 30 The major catechins are (À) epigallocatechin-3-gallate (EPI), (À) epicathin-3-gallate, (À) epigallocatechin, and (À) epicatechin.…”

Metabolism of Hop-Derived Bitter Acids

“…During brewing, the relatively insoluble α-acids are transformed into their corresponding mixture of beer-soluble diastereomeric pairs of iso-α-acids (cis-and trans-isomers), thus resulting in six iso-α-acids originating from the three main α-acids (Figure 1). Next to their application in beers, an increase in global research interest in the health-beneficial aspects of hop-derived bitter acids has been observed 1,2 as evidenced by the increasing number of reports on various promising bioactivities with IC 50 values in the lower micromolar range (anti-inflammatory 3,4 and antiangiogenic properties, 5,6 improving lipid profiles, 7,8 and counteracting diabetes type 2). 9 In comparison to the growing knowledge on their healthbeneficial effects, little is known about the absorption, distribution, metabolism, and excretion (ADME) of these compounds.…”