Xanthohumol as a cancer chemopreventive agent
Table of Contents
Xanthohumol is a prenylated chalcone derived from hop (Humulus lupulus L.). In hop, the yellow compound (Greek: xantho = yellow) is found in high quantities in the lupulin glands of the female inflorescence.
Xanthohumol is part of our diet mainly in the form of beer or beer mix drinks. Due to the thermal conversion of Xanthohumol to the isoflavanone isoxanthohumol during the brewing process, the concentration of xanthohumol in beer, however, is very low (approximately 0.1 mg/l in German style lager beers).
Since the 1990s, interest in health-promoting activities of hop-derived constituents, including prenyl flavonoids and hop bitter acids, increased constantly, and scientific investigations were initialized worldwide (reviewed in Ref. 1-4).
In vitro investigations
In 2002, we identified xanthohumol as a broad-spectrum cancer chemopreventive agent acting by multiple mechanisms relevant for the prevention of carcinogenesis in the initiation, promotion and progression phase (5).
Xanthohumol is able to scavenge a variety of physiological relevant radicals including peroxyl-, hydroxyl-, and superoxide anion-radicals. Anti-initiating mechanisms also include the modulation of enzymes involved in carcinogen metabolism and detoxification.
Xanthohumol was characterized as an effective anti-inflammatory agent. It was found to inhibit both cyclooxygenases Cox-1 and Cox-2 and was shown to decrease LPS-mediated iNOS induction in cultured Raw 264.7 murine macrophages.
Using alkaline phosphatase induction in the Ishikawa cell line, xanthohumol was identified as an anti-estrogen without possessing estrogenic potential. It also inhibits aromatase (Cyp19) activity.
With respect to anti-proliferative mechanisms, XN was shown to decrease human recombinant DNA polymerase alpha activity, and to inhibit DNA synthesis in MDA MB 435 human breast cancer cells. Poly(ADP-ribose)polymerase (PARP) cleavage, activation of caspases-3, -7, -8, and 9 and downregulation of Bcl-2 protein expression were found to contribute to apoptosis induction in cultured human colon cancer cells (6).
Importantly, xanthohumol at nanomolar concentrations prevented carcinogen-induced preneoplastic lesions in mouse mammary gland organ culture (MMOC), providing a first direct indication for its chemopreventive potential (5).
Bioavailability and metabolism
We investigated the oral bioavailability of xanthohumol in a kinetic experiment. Xanthohumol was applied by gavage to female Sprague Dawley (SD) rats at a single dose of 1000 mg/kg body weight (bw).The Xanthohumol-4’-O-glucuronide was identified as the major metabolite with a Tmax at 4 h and a Cmax of 3.1µM, whereas unmetabolized xanthohumol was detectable with a Cmax of 0.34µM (equal to 0.12µg/ml) 4 h post-administration. About 90% of the applied xanthohumol was recovered unmetabolized from faeces after 24 and 48h. Sixteen novel metabolites were isolated from faecal samples in addition to six previously known metabolites (7).
Subchronic toxicity and in vivo activities
Safety after long-term application is a very important issue for compounds intended for the prevention of chronic diseases. Hussong et al. demonstrated weak hepatotoxicity when xanthohumol was applied for four weeks at a daily dose of 1000 mg/kg per day to female SD rats (8). At a 10-fold lower concentration (in drinking water), however, xanthohumol did not show any toxic effects, but reduced malondialdehyde levels as an indication of oxidative stress induced by a single s.c. application of LPS (10 mg/kg bw).
Anti-estrogenic effects of xanthohumol were confirmed in vivo. In an uterotrophy assay with prepubertal rats, xanthohumol treatment (100 mg/kg bw/day) lowered unstimulated as well as ethinylestradiol-induced uterine weights by about 30% (11). Xanthohumol did not cause any adverse effect on female reproduction and on the development of offspring when given either for four weeks prior to or during mating, gestation and nursing. Treatment of male rats prior to mating significantly (p = 0.027) increased the sex ratio of male to female offspring (9).
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