Elsevier

Phytochemistry

Volume 65, Issue 10, May 2004, Pages 1317-1330
Phytochemistry

Molecules of Interest
Xanthohumol and related prenylflavonoids from hops and beer: to your good health!

https://doi.org/10.1016/j.phytochem.2004.04.025Get rights and content

Abstract

Xanthohumol (3′-[3,3-dimethyl allyl]-2′,4′,4-trihydroxy-6′-methoxychalcone) is the principal prenylated flavonoid of the female inflorescences of the hop plant (`hops'), an ingredient of beer. Human exposure to xanthohumol and related prenylflavonoids, such as 8-prenylnaringenin and isoxanthohumol, is primarily through beer consumption. Xanthohumol has been characterized a `broad-spectrum' cancer chemopreventive agent in in vitro studies, while 8-prenylnaringenin enjoys fame as the most potent phytoestrogen known to date. These biological activities suggest that prenylflavonoids from hops have potential for application in cancer prevention programs and in prevention or treatment of (post-)menopausal `hot flashes' and osteoporosis. Xanthohumol and 8-prenylnaringenin are metabolized into many flavonoid derivatives with modified 3,3-dimethyl allyl (prenyl) moieties. Xanthohumol is formed in lupulin glands by a specialized branch of flavonoid biosynthesis that involves prenylation and O-methylation of the polyketide intermediate chalconaringenin. Although a lupulin gland-specific chalcone synthase is known, the aromatic prenyltransferase and O-methyltransferase participating in xanthohumol have not been identified. The prenylflavonoid pathway is a possible target for breeding or biotechnological modification of hops with the aim of increasing xanthohumol levels for beer brewing and 8-prenylnaringenin levels for pharmaceutical production.

This review provides an overview of the chemistry, biological activities, and biotechnological aspects of xanthohumol, 8-prenylnaringenin, and other prenylated flavonoids from hops, Humulus lupulus L.

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Introduction

Xanthohumol is a structurally simple prenylated chalcone that occurs only in the hop plant, Humulus lupulus L. (Cannabaceae), where it is the principal prenylflavonoid of the female inflorescences (usually referred to as `hops' or `hop cones'). Hops are used to add bitterness and flavor to beer, and therefore the main dietary source of xanthohumol and related prenylflavonoids is beer. Xanthohumol and other prenylated chalcones have received much attention in recent years as cancer chemopreventive agents, while 8-prenylnaringenin, an isomerization product of desmethylxanthohumol also present in beer, enjoys fame as the most potent phytoestrogen isolated to date. These exciting biological activities may lead to biomedical application of xanthohumol and 8-prenylnaringenin in the future. Furthermore, hop prenylflavonoids are currently tested in many academic and industrial laboratories for other biological activities. At the same time, hop-containing herbal preparations are being marketed for breast enlargement in women, without proper testing of efficacy and toxicity. The use of hops in herbal preparations represents a small market and does not seem to be promoted by the hop growing industry. However, hop growers are very interested in alternative applications for hops and its constituents in view of the continuing trend of decreasing market prices of hops and improving agricultural production methods.

The purpose of this review is to provide an overview of the chemistry, biological activities, and biotechnological aspects of xanthohumol and other prenylated flavonoids from hops. Biosynthetically related to the prenylated flavonoids are the prenylated acylphloroglucinols, i.e., humulones (α-acids) and lupulones (β-acids), which represent the commercial value of hops as bittering substances for the beer industry but potential biomedical applications have not yet been identified for this group of terpenophenolics. Hops are also rich sources of flavonol glycosides and condensed tannins: these groups of flavonoids will not be treated either as they are widely distributed in the plant kingdom.

Section snippets

Distribution and chemotaxonomic significance of xanthohumol and related flavonoids

The distribution of xanthohumol is limited to and ubiquitous within H. lupulus. Xanthohumol is secreted as part of the hop resin (`lupulin') by glandular trichomes found on the adaxial surfaces of cone bracts. It is also found in the trichomes on the underside of young leaves. Xanthohumol is the main prenylflavonoid of hops (0.1–1% on dry weight); in the resin, xanthohumol is accompanied by at least 13 related chalcones (Table 1), all of which occur at 10–100-fold lower concentrations relative

Isolation and chemical synthesis

Xanthohumol was first isolated, partially characterized and named by Power et al. (1913). They also obtained a related substance which they called humulol, which was later identified as the flavanone, isoxanthohumol, by Verzele et al. (1957). In the years following 1957, there remained some doubt as to the position of the prenyl substituent relative to the methoxy group in xanthohumol. Two independent groups were finally able to confirm Verzele's original structure as the correct structure of

Dietary exposure

Beer is the most important dietary source of xanthohumol and related prenylflavonoids. The average person in the United States consumed 225 mL of beer per day in 2001 (USDA, 2003). Based on the assumption that this amount was consumed as US major brand lager/pilsner beers, the daily intake of total prenylflavonoids would be about 0.14 mg, with isoxanthohumol being the principal dietary prenylflavonoid (Table 2). Although xanthohumol is the major prenylflavonoid in hops, it is generally a minor

Bioavailability and metabolism

Absorption, metabolism, and renal excretion of xanthohumol were studied in rats by Yilmazer (2001). After oral administration of xanthohumol to male rats (50 mg/kg), xanthohumol was detected in plasma mainly in the form of two mono-glucuronides whose maximum concentrations reached 180 and 65 nM after 4 h. The cumulative amounts of both xanthohumol glucuronides excreted in the urine reached a plateau at 12 h after oral administration and accounted for 0.3% and 0.05% of the administered dose. The

Cancer-related bioactivities

Cancer chemoprevention is different from cancer treatment in that it is aimed at modulation of pathways that are relevant to carcinogenesis with the effect that tumor formation is inhibited. Ideally, cancer prevention is achieved by long-term exposure to non-toxic agents, preferably as part of certain food products. Xanthohumol is the best studied cancer chemopreventive phytochemical isolated from hops. We show in the following paragraphs that xanthohumol is a `broad-spectrum' cancer

Antioxidant activities

Flavonoids represent the largest group of plant polyphenols. Their dietary intake through fruits and vegetables has been associated with a lower incidence of cardiovascular disease (Hertog et al., 1993). This and many other studies suggest that dietary flavonoids may have beneficial effects on human health and disease prevention, which is primarily attributed to their antioxidant properties. While commonly occurring flavonols have received much attention as natural antioxidants, only a few

Estrogenic activity

The estrogenic effects of hops have been recognized for decades (Zenisek and Bednar, 1960). Haensel and Schulz (1988) suspected that their desmethylxanthohumol was identical with an earlier reported `pro-estrogen' from hops, from which the `hop-estrogens', 6-, and 8-prenylnaringenin, are formed by spontaneous or base-catalyzed cyclization. The active estrogenic principle remained unclear, however, until bioassay-guided fractionation of hop extracts led to the isolation 8-prenylnaringenin as a

Biosynthesis of prenylflavonoids

Although prenylflavonoids like xanthohumol have a restricted distribution in nature, flavonoids are ubiquitous in higher plants and the biosynthetic pathway leading to these compounds is well characterized at both genetic and enzymatic levels (Forkmann and Martens, 2001; Winkel-Shirley, 2002). The first step in flavonoid biosynthesis is the condensation of p-coumaroyl CoA with three molecules of malonyl CoA to give chalconaringenin (also called naringenin chalcone), a reaction catalyzed by

Chemical ecology of prenylflavonoids

Prenylflavonoids and bitter acids accumulate in lupulin glands that cover bracts (also called scales) of female hop cones (Fig. 1). The biosynthetic pathways leading to these compounds are highly active in such glands with both chs_H1 and valerophenone synthase, the polyketide synthase involved in bitter acid formation (i.e., humulone), expressed at high levels (Okada and Ito, 2001; Matousek et al., 2002a). Since hops also contain kaempferol and quercetin glycosides (Sägesser and Deinzer, 1996

Opportunities for metabolic engineering of prenylflavonoids

Beer is the alcoholic beverage of choice in many parts of the world and may represent a vehicle for increasing the consumption of natural products with antioxidant and other health-promoting properties. We should note, however, that the health benefits of moderate amounts of beer and other alcoholic beverages must be balanced against the health problems associated with alcohol abuse. Based on the health-promoting properties of xanthohumol, increasing the concentration of this compound in beer

Acknowledgements

We thank Annett Kohlberg (Institut fuer Pflanzenbiochemie, Halle, Germany) for photographs of the hops cone and lupulin glands, and Dr. Cristobal Miranda and Dr. Jane Higdon (Oregon State University) for critical reading of the manuscript. Generous support from Hopsteiner (New York) is also gratefully acknowledged.

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