Hops

Scientific Name(s): Humulus lupulus L. Family: Cannabaceae (marijuana family)

Common Name(s): Hops

Uses

Hops have been used for flavoring; hops and lupulin have been used as a digestive aid, for mild sedation, diuresis, and treating menstrual problems, but no clinical studies are available to confirm these uses.

Dosing

Hops has been used as a mild sedative or sleep aid, with the dried strobile given in doses of 1.5 to 2 g. An extract combination with valerian, Ze 91019 ( ReDormin , Ivel ) has been studied at a hops dose of 60 mg for insomnia.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

There are no reported side effects when used in moderation.

Toxicology

Malignant hyperthermic reactions have been observed in dogs that consumed boiled hops residues. A wide safety margin for humans has been extrapolated from animal experiments.

Botany

Hops is a perennial climbing vine extensively cultivated worldwide. Male and female flowers are located on separate plants; the cone-shaped fruits are known as strobiles, which are collected in the fall and carefully dried.

History

Hops have been used for centuries to flavor and preserve beer. The bitter, aromatic taste of beer is mostly due to the hops content. Hops extracts are also used for other flavoring purposes in the food industry. Medical uses of hops and lupulin include aiding digestion, mild sedation, diuresis, and treating menstrual problems. Hops pickers have reported sedation during harvest, and hops flowers have been added to pillows for relief of nervous conditions.

Chemistry

The most characteristic constituents of hops are the bitter principles, known as alpha- and beta-acids. In the plant the alpha-acids occur as humulone, cohumulone, and adhumulone. 1 , 2 During the brewing process, these compounds are isomerized to the iso-alpha-acid series of compounds, that possess the bitter taste. 3 The beta-acid series of compounds include lupulone and congeners; 1 , 2 this series is destroyed during brewing. The relative proportions of the bitter acids affect the quality of the hops, and many methods have been developed for quantifying hop acids in different varieties, including nuclear magnetic resonance (NMR) 1 , 4 and high-pressure liquid chromatography (HPLC). 5 , 6 The complex profile of hop acids is dependent on genetics, cultivation, and storage conditions. Long-term storage of hops leads to major deterioration in quality.

The essential oils of hops are less characteristic but are still important to hop quality. Over 100 volatile compounds have been identified, with gas chromatography and gas chromatography-mass spectroscopy (GC-MS) being key techniques for analysis. 7 , 8 Caryophyllene, beta-myrcene, and humulene are the most abundant constituents of hops volatile oils.

A third group of hops constituents is the prenylflavonoids. Xanthohumol is the dominant prenylflavonoid of hops, 9 with 8-prenylnaringenin also of importance. 10 A GC-MS method has been developed for the latter, 10 while liquid chromatography-tandem mass spectrometry (LC-MS) has been used to directly quantify prenylflavonoids and their isomerization products in beer and hops extracts. 11 The variation in prenylflavonoids between hops varieties has also been studied. 12 The fate of xanthohumol as hops is processed into beer has been studied; 20% to 30% is converted to isoxanthohumol. 13 The metabolism of xanthohumol in rat and human liver microsomes has also been characterized. 14 , 15

Uses and Pharmacology

Sedative

The observation that hops pickers often experienced sedation prompted investigation of hops for sedative principles.

Animal data

The compound 2-methyl-3-buten-2-ol was isolated and found to reduce the spontaneous movement of rats when given intraperitoneally. 16 The small amounts found in hops 7 makes it unlikely that this compound completely explains hops sedation.

Clinical data

Hops is often included in combination with valerian in sleep aids; studies of such products have found that valerian is more important to the pharmacologic activity than hops. 17 , 18 , 19

Phytoestrogenic
Animal data

8-prenylnaringenin was found to be a potent estrogen receptor agonist in estrogen-responsive cells, while other hops phenolics were less active (isoxanthohumol, 6-prenylnaringenin) or had no activity (xanthohumol). 20 The amounts present in beer were considered to be too small to cause estrogenic effects. Estrogenic effects in vivo were observed in mice given isolated 8-prenylnaringenin in drinking water at 100 mcg/mL, using uterine vascular permeability as an endpoint. 21

Clinical data

Estrogenic effects were also observed in evaluation of hops extract for the treatment of menstrual symptoms. 22 Use of hops in breast enhancement products was cause for concern. 23 , 24

Cancer chemoprevention

Hops bitter acids have substantial effects on metabolic enzymes.

Animal data

Colupulone adsorbed on brewers' yeast was found to induce cytochrome P-450 3A in mice, an enzyme capable of N-demethylation of ethylmorphine. 25 , 26 However, short-term assays for aflatoxin or benzpyrene activation through colupulone induction of CYP450 did not find a change in mutagen activation. 27 While beer and other alcoholic beverages have been found to inhibit mutagenesis induced by carcinogens in an Ames test, the compounds responsible were not identified. 28 In a later study, several hops prenylflavonoids inhibited carcinogenic amine activation by CYP1A2. 29

Humulone was identified as the active hops constituent that inhibited phorbol ester-induced inflammation in mice. 30 The same group later demonstrated that humulone was active in blocking tumor promotion in the classical two-stage model of carcinogenesis. 31 Several different hops prenylflavonoids demonstrated antiproliferative and cytotoxic effects in breast, colon, and ovarian human cancer cell lines. 32 8-prenylnaringenin was shown to upregulate the cadherin and catenin genes in human breast cancer cells. 33 A comprehensive evaluation of xanthohumol as a cancer chemopreventative agent found that it warented clinical investigation because it had distinct activities at the initiation, promotion, and progression stages of carcinogenesis. 34

Clinical data

Research reveals no clinical data regarding the use of hops for cancer chemoprevention.

Antibiotic and other

The hop bitter acids have antibacterial and antifungal activity important for the preservative function of hops in beer. When tested at the normal pH of beer (4.0), isohumulone inhibited bacterial growth at concentrations at which it is normally found in beer. 35 The prenylflavonoids of hops were shown to be more effective antioxidants than nonprenylated flavonoids. 36 Humulone potently suppressed COX-2 gene expression at the level of transcription. 37 Xanthohumols inhibited diacylglycerol acyltransferase, an effect of possible importance in lipid metabolism. 38 Polyphenolics of hops were shown to inhibit alpha-acid oxidase activity, thereby providing an internal control over hops' acid metabolism. 39 Hops proanthocyanidins were shown to inhibit neuronal nitric oxide synthetase and efficiently scavenge reactive nitrogen species. 40

Dosage

Hops has been used as a mild sedative or sleep aid, with the dried strobile given in doses of 1.5 to 2 g. An extract combination with valerian, Ze 91019 ( ReDormin , Ivel ) has been studied at a hops dose of 60 mg for insomnia. 41

Pregnancy/Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Research reveals little or no information regarding adverse reactions with the use of hops.

Toxicology

As an historical food constituent, hops has “generally recognized as safe” (GRAS) status by the FDA, however; use of medicinal quantities of hops may pose more risk than common levels of exposure in food use. Dogs appear to be somewhat sensitive to hops compounds. A malignant hyperthermic reaction was observed in 5 dogs who consumed boiled hops residues used in home brewing. 42 A subchronic toxicity study of the hops alpha-acids was conducted in dogs; while high doses induced vomiting, the animals generally tolerated lower doses without ill effects. A wide safety margin for humans was extrapolated from this experiment. 43

Bibliography

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3. Carson JF. The alkaline isomerization of humulone. J Am Chem Soc . 1952;74:4615-4620.
4. Molyneux RJ, Wong Y. Nuclear magnetic resonance spectroscopic determination of alpha- and beta-acid homolog composition in hops. J Agric Food Chem . 1975;23:1201-1204.
5. De Cooman L, Everaert E, De Keukeleire D. Quantitative analysis of hop acids, essential oils, and flavonoids as a clue to the identification of hop varieties. Phytochem Anal . 1998;9:145-150.
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7. Eri S, Khoo BK, Lech J, Hartman TG. Direct thermal desorption-gas chromatography and gas chromatography-mass spectrometry profiling of hop ( Humulus lupulus L.) essential oils in support of varietal characterization. J Agric Food Chem . 2000;48:1140-1149.
8. Steinhaus M, Scheiberle P. Comparison of the most odor-active compounds in fresh and dried hop cones ( Humulus lupulus L. variety spalter select) based on GC-olfactometry and odor dilution techniques. J Agric Food Chem . 2000;48:1776-1783.
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10. Tekel' J, De Keukeleire D, Rong H, Daeseleire E, Van Peteghem C. Determination of the hop-derived phytoestrogen, 8-prenylnaringenin, in beer by gas chromatography/mass spectrometry. J Agric Food Chem . 1999;47:5059-5063.
11. Stevens JF, Taylor AW, Deinzer ML. Quantitative analysis of xanthohumol and related prenylflavonoids in hops and beer by liquid chromatography-tandem mass spectrometry. J Chromatogr A . 1999;832:97-107.
12. Stevens JF, Taylor AW, Nickerson GB, et al. Prenylflavonoid variation in ( Humulus lupulus ): distribution and taxonomic significance of xanthogalenol and 4′-O-methylxanthohumol. Phytochemistry . 2000;53:759-775.
13. Stevens JF, Taylor AW, Clawson JE, Deinzer ML. Fate of xanthohumol and related prenylflavonoids from hops to beer. J Agric Food Chem . 1999;47:2421-2428.
14. Yilmazer M, Stevens JF, Deinzer ML, Buhler DR. In vitro biotransformation of xanthohumol, a flavonoid from hops ( Humulus lupulus ), by rat liver microsomes. Drug Metab Dispos . 2001;29:223-231.
15. Yilmazer M, Stevens JF, Buhler DR. In vitro glucuronidation of xanthohumol, a flavonoid in hop and beer, by rat and human liver microsomes. FEBS Lett . 2001;491:252-256.
16. Wohlfart R, Hänsel R, Schmidt H. The sedative-hypnotic action of hops. 4. Pharmacology of the hop substance 2-methyl-3-buten-2-ol (in German). Planta Med . 1983;48:120-123.
17. Vonderheid-Guth B, Todorova A, Brattström A, Dimpfel W. Pharmacodynamic effects of valerian and hops extract combination (Ze 91019) on the quantitative-topographical EEG in healthy volunteers. Eur J Med Res . 2000;5:139-144.
18. Fussel A, Wolf A, Brattsröm A. Effect of a fixed valerian-Hop extract combination (Ze 91019) on sleep polygraphy in patients with non-organic insomnia: a pilot study. Eur J Med Res . 2000;5:385-390.
19. Müller CE, Schumacher B, Brattsröm A, Abourashed EA, Koetter U. Interactions of valerian extracts and a fixed valerian-hop extract combination with adenosine receptors. Life Sci . 2002;71:1939-1949.
20. Milligan SR, Kalita JC, Heyerick A, Rong H, De Cooman L, De Keukeleire D. Identification of a potent phytoestrogen in hops ( Humulus lupulus L.) and beer. J Clin Endocrinol Metab . 1999;84:2249-2252.
21. Milligan SR, Kalita JC, Pocock V, et al. The endocrine activities of 8-prenylnaringenin and related hop ( Humulus lupulus L.) flavonoids. J Clin Endocrinol Metab . 2000;85:4912-4915.
22. Coldham NG, Sauer MJ. Identification, quantitation and biological activity of phytoestrogens in a dietary supplement for breast enhancement. Food Chem Toxicol . 2001;39:1211-1224.
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24. Liu J, Burdette JE, Xu H, et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms. J Agric Food Chem . 2001;49:2472-2479.
25. Mannering GJ, Shoeman JA, Deloria LB. Identification of the antibiotic hops component, colupulone, as an inducer of hepatic cytochrome P-4503A in the mouse. Drug Metab Dispos . 1992;20:142-147.
26. Mannering GJ, Shoeman JA, Shoeman DW. Effects of colupulone, a component of hops and brewers yeast, and chromium on glucose tolerance and hepatic cytochrome P450 in nondiabetic and spontaneously diabetic mice. Biochem Biophys Res Commun . 1994;200:1455-1462.
27. Shipp EB, Mehigh CS, Helferich WG. The effect of colupulone (a HOPS beta-acid) on hepatic cytochrome P-450 enzymatic activity in the rat. Food Chem Toxicol . 1994;32:1007-1014.
28. Arimoto-Kobayashi S, Sugiyama C, Harada N, Takeuchi M, Takemura M, Hayatsu H. Inhibitory effects of beer and other alcoholic beverages on mutagenesis and DNA adduct formation induced by several carcinogens. J Agric Food Chem . 1999;47:221-230.
29. Miranda CL, Yang Y, Henderson MC, et al. Prenylflavonoids from hops inhibit the metabolic activation of the carcinogenic heterocyclic amine 2-amino-3-methylimidazo[4, 5-f]quinoline, mediated by cDNA-expressed human CYP1A2. Drug Metab Dispos . 2000;28:1297-1302.
30. Yasukawa K, Yamaguchi A, Arita J, Sakurai S, Ikeda A, Takido M. Inhibitory effect of edible plant extracts on 12-O-tetradecanoylphorbol-13-acetate-induced ear edema in mice. Phytother Res . 1993;7:185-189.
31. Yasukawa K, Takeuchi M, Takido M. Humulon, a bitter in the hop, inhibits tumor promotion by 12-O- tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Oncology . 1995;52:156-158.
32. Miranda CL, Stevens JF, Helmrich A, et al. Antiproliferative and cytotoxic effects of prenylated flavonoids from hops ( Humulus lupulus ) in human cancer cell lines. Food Chem Toxicol . 1999;37:271-285.
33. Rong H, Boterberg T, Maubach J, et al. 8-Prenylnaringenin, the phytoestrogen in hops and beer, upregulates the function of the E-cadherin/catenin complex in human mammary carcinoma cells. Eur J Cell Biol . 2001;80:580-585.
34. Gerhauser C, Alt A, Heiss E, et al. Cancer chemopreventive activity of xanthohumol, a natural product derived from hop. Mol Cancer Ther . 2002;1:959-969.
35. Simpson WJ, Smith AR. Factors affecting antibacterial activity of hop compounds and their derivatives. J Appl Bacteriol . 1992;72:327-334.
36. Rodriguez RJ, Miranda CL, Stevens JF, Deinzer ML, Buhler DR. Influence of prenylated and non-prenylated flavonoids on liver microsomal lipid peroxidation and oxidative injury in rat hepatocytes. Food Chem Toxicol . 2001;39:437-445.
37. Yamamoto K, Wang J, Yamamoto S, Tobe H. Suppression of cyclooxygenase-2 gene transcription by humulon of beer hop extract studied with reference to glucocorticoid. FEBS Lett . 2000;465:103-106.
38. Tabata N, Ito M, Tomoda H, Ōmura S. Xanthohumols, diacylglycerol acyltransferase inhibitors, from Humulus lupulus . Phytochemistry . 1997;46:683-687.
39. Williams EA, Menary RC. Polyphenolic inhibitors of alpha-acid oxidase activity. Phytochemistry . 1988;27:35-39.
40. Stevens JF, Miranda CL, Wolthers KR, Schimerlik M, Deinzer ML, Buhler DR. Identification and in vitro biological activities of hop proanthocyanidins: inhibition of nNOS activity and scavenging of reactive nitrogen species. J Agric Food Chem . 2002;50:3435-3443.
41. Fussel A, Wolf A, Brattstrom A. Effect of a fixed valerian-hop extract combination (Ze 91019) on sleep polygraphy in patients with non-organic insomnia: a pilot study. Eur J Med Res . 2000;5:385-390.
42. Duncan KL, Hare WR, Buck WB. Malignant hyperthermia-like reaction secondary to ingestion of hops in five dogs. J Am Vet Med Assoc . 1997;210:51-54.
43. Chappel CI, Smith SY, Chagnon M. Subchronic toxicity study of tetrahydroisohumulone and hexahydroisohumulone in the beagle dog. Food Chem Toxicol . 1998;36:915-922.

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