Prof. Dr. Jan Frank from the University of Hohenheim studies the health-promoting potential of secondary plant metabolites. Plants produce secondary metabolites in metabolic pathways that are not essential to the functioning of plants, but give them survival advantages. Some secondary metabolites are used for defence purposes, others protect plants against parasites, microorganisms or UV radiation. Still others attract pollinators. Humans use secondary plant metabolites such as atropine and digitalis for medical treatment, or nicotine, as a stimulant drug. The quantity of such compounds varies considerably between plants. Professor Frank has chosen to research hop prenylflavonoids, which are naturally only present in tiny quantities (1%) in the cones of female hop plants. Isolating sufficiently high quantities is therefore a time-consuming process. Professor Frank and his project partners from the University Hospital in Tübingen, Dr. Christian Busch and Dr. Dr. Sascha Venturelli, therefore spent 50,000 euros on the third-party extraction of sufficient quantities of specific, highly pure hop prenylflavonoids.

It will be money well spent if it confirms what previous laboratory investigations involving standardised human cell lines and primary patient materials have suggested. Prenylflavonoids appear to stimulate the immune system and impede the growth of tumour cells. These characteristics might be that certain prenylflavonoids might one day be used for treating and possibly also preventing cancer. The compounds were among a large number of secondary plant metabolites that Frank’s cooperation partners at the University of Tübingen screened in their search for potential anti-cancer compounds. However, the results cannot simply be transferred to the situation in humans. As Frank explains, "All previous experiments were performed under optimised cell culture conditions. However, in the human body, cells are in contact with many other cell types and are part of a complex metabolic machinery.” In addition, when administered orally, only a small fraction of administered compounds is absorbed in the intestine. “In general, all secondary plant metabolites are poorly absorbed. They are foreign substances that cannot be used as direct substrates for producing energy or as co-enzymes for metabolic processes. As the body does not really need them, prenylflavonoids are transported to the liver, where they are metabolised and excreted,” says Frank.

Frank came across a similar situation in his research with curcumin, a secondary plant metabolite of turmeric, an ingredient used in curry that also has health benefits. “We found that 99.9 percent of all curcumin is metabolised in the liver. Researchers are currently investigating whether metabolites that circulate in the blood have an effect. We also want to study this in prenylflavonoids,” says Frank. However, these projects are currently of minor importance for him. Frank is mainly interested in finding a way of improving the absorption rate of secondary plant metabolites and hence their potential health benefits.

Frank works with AQUANOVA AG from Darmstadt and uses the company’s micelle technology for his research. AQUANOVA produces so-called product micelles from complex, food-grade carrier substances that have a lipophilic component (tail) on the inside and a hydrophilic component on the outside. The micelles are formulated and manufactured in such a way that they are stable in the acidic environment of the stomach with its low pH and arrive intact in the small intestine. “This product micelle has a natural model. Bile salts, which are formed in the liver and secreted by the gall bladder, allow micelles of lipid-soluble substances, e.g. fat-soluble vitamins for example, to form and be absorbed in the small intestine. Bile salts form a shell of emulsifiers around these fat-soluble nutrients in the same way as polysorbates in product micelles enclose secondary plant metabolites such as prenylflavonoids or curcumin,” said Frank.

Frank has already achieved a 185-fold increase in curcumin's absorption rate. He has also been able to demonstrate this effect in a clinical trial involving healthy volunteers. Frank now hopes to achieve equally good results with prenylflavonoids. “We have carried out a bioavailability study with micelles and been able to measure some effects, which means that we actually found prenylflavonoids in the blood,” said the researcher. Frank, Venturelli and Busch now plan to carry out a bioactivity study involving healthy volunteers who will take capsules containing prenylflavonoid micelles for a period of four to eight weeks. “We will examine their blood for the presence of functional parameters such as blood lipids and immune system markers,” says Frank.

What exactly happens with the micelles in the epithelium of the small intestine has yet to be explored. “We are currently looking for an experimental approach aimed at finding out whether the micelles remain intact and are potentially internalised as a whole. There is evidence that emulsifiers are not absorbed via the intestinal epithelium. But we do not know whether this is also the case with micelles. We are looking for a research partner with skills in electron microscopy to help us,” said Frank. He is also interested in differences in the intestinal barrier. “Many cancers are characterised by altered metabolic processes, and the intestinal mucosa might also be changed, resulting in better or worse absorption of secondary plant metabolites.”

In his studies, Frank uses native secondary plant compounds that he extracts from hop plants rather than synthetic counterparts. This is for cost reasons, but also has a practical benefit. “If we are thinking about using prenylflavonoids for the prevention of cancer and adding them to functional foods, I feel it is important to use natural hop extracts that are rich in prenylflavonoids. I am sure they will be more widely accepted. An obvious example of a similar functional food is alcohol-free beer, which is produced using hop varieties with a particularly high concentration of prenylflavonoids. The compound could also be added to beverages. Such an application would of course be extremely interesting for the beer brewing industry which has already placed on the market beverages with potentially health-promoting secondary plant metabolites and is constantly looking for new innovations. Therefore, Venturelli’s, Busch’s and Frank’s interuniversity research project is supported by the Committee for Promoting Science of the German Brewery Industry (WiFö) with funds of 145,000 euros. The project also receives funding through the medical faculty of the University of Tübingen, taken partly from German Excellence Initiative funds.