Xanthohumol does not affect the composition of rat intestinal microbiota.

Xanthohumol (XN), a prenylated chalcone, has been proposed to have beneficial effects on human health, including antimicrobial activity. To clarify whether the exposure to XN has an impact on the composition of the intestinal microbiota, 100 mg XN/kg body weight was given daily to rats for 4 wk. Diversity of the fecal microbial community was analyzed using PCR-DGGE. Although intact XN was detected in the feces of the rats at a concentration of up to 2.3 mg/g fecal dry weight, major shifts in the PCR-DGGE patterns in response to this flavonoid were not observed. The similarity index decreased slightly from 70 to 62% for the XN-treated rats and from 71 to 63% for the untreated animals. Thus, changes in the rat fecal microbiota observed in the course of the XN application are most likely due to intraindividual variability. However, the water content of the feces increased significantly during the XN treatment period.

A safety study of oral xanthohumol administration and its influence on fertility in Sprague Dawley rats.

Xanthohumol (XN) is a prenylated chalcone, which has been shown to possess a broad range of potential cancer preventive and additional biological activities. In the present study, we have determined the subchronic 4-wk toxicity of XN and monitored its influence on fertility and development of offspring in two fertility studies. Four-week-old female Sprague Dawley (SD) rats were treated with 0.5% XN in the diet or with 1,000 mg XN/kg body weight (b.w.) per day by gavage for 28 days. No remarkable treatment-related changes in general appearance and b.w. occurred during the study. After autopsy, liver, kidney, lung, heart, stomach, and spleen were examined macroscopically and histopathologically. Relative liver weights of animals in both treatment groups were significantly reduced by 30--40% in comparison with the control group, indicating weak hepatotoxicity. Also, mammary glands of treated rats appeared less developed compared to the controls. Consequently, we investigated the influence of XN on rat reproduction. In two fertility studies, XN (100 mg/kg b.w. per day), given either for 4 wk prior to or during mating, gestation, and nursing, did not cause any adverse effects on female reproduction and the development of offspring. Noteworthy, treatment of male rats prior to mating significantly (p=0.027) increased the sex ratio of male to female offspring. Overall, lifelong treatment at a daily dose of 100 mg/kg b.w. in a two-generation study did not affect the development of SD rats.

Xanthohumol, a prenylated chalcone from hops, modulates hepatic expression of genes involved in thyroid hormone distribution and metabolism.

In the present study, we analyzed the influence of xanthohumol (XN) on thyroid hormone (TH) distribution and metabolism in rats. A potent and selective competition of XN for thyroxine (T4) binding to transthyretin (IC(50)=1 microM at 1.7 nM [(125)I]T4) was found in human and rat sera in vitro. Female rats treated orally with XN showed increased hepatic expression of T4-binding globulin and decreased transthyretin and albumin. Thyrotropin levels and hepatic type 1 deiodinase activity were moderately increased. Northern blot analysis revealed diminished expression of liver sulfotransferase (Sult1a1) and uridine-diphosphate glucuronosyltransferase (Ugt1a1) after XN treatment. The transcript levels of constitutive androstane receptor (CAR), known to be involved in regulation of enzymes metabolizing hormones, drugs and xenobiotics, was lower in rats treated with >10 mg XN/kg body weight per day. Immunoblot analysis indicates reduced amounts of CAR protein. The phenobarbital-inducible cytochrome P450 mRNA level was decreased in rats treated with >10 mg XN/kg/day, in agreement with reduced CAR protein. Although only moderate changes in TH serum levels were observed, the XN-dependent altered expression of components involved in TH homeostasis might be important not only for hormone metabolism, but also for hepatic phase I and II elimination of drug metabolites and xenobiotics.

Variability of the human aryl hydrocarbon receptor nuclear translocator (ARNT) gene.

The aryl hydrocarbon receptor nuclear translocator (ARNT) plays an essential role in vertebrate transcriptional regulation as the common subunit of transcriptionally active complexes like the aryl hydrocarbon receptor (AHR)/ARNT heterodimer and hypoxia-inducible factor 1, mediating cellular responses to certain xenobiotics and to hypoxia, respectively. A cohort of healthy Caucasian volunteers was screened for genetic variations of ARNT. Six polymorphic sites could be identified, a variation in a G-stretch upstream of the ATG translation start site, a frequent silent mutation (G567C), two polymorphic sites in intron 9, and two single nucleotide substitutions leading to amino acid exchanges, G1531A (D511N) and T1551G (D517E). The frequencies were 0.005 for the Asn-coding allele and for the Glu-coding allele, respectively, with no linkage between these two mutations. Although no significant correlation with activities of CYP1A2, which is under regulatory control of the AHR/ARNT transcription complex, could be established, metabolic or pathological phenotypes may be associated with these variations.