DESIGNER Extracts as Tools to Balance Estrogenic and Chemopreventive Activities of Botanicals for Women’s Health

Abstract

Botanical dietary supplements contain multiple bioactive compounds that target numerous biological pathways. The lack of uniform standardization requirements is one reason that inconsistent clinical effects are reported frequently. The multifaceted biological interactions of active principles can be disentangled by a coupled pharmacological/phytochemical approach using specialized (“knock-out”) extracts. This is demonstrated for hops, a botanical for menopausal symptom management. Employing targeted, adsorbent-free countercurrent separation, Humulus lupulus extracts were designed for pre- and postmenopausal women by containing various amounts of the phytoestrogen 8-prenylnaringenin (8-PN) and the chemopreventive constituent xanthohumol (XH). Analysis of their estrogenic (alkaline phosphatase), chemopreventive (NAD(P)H-quinone oxidoreductase 1 [NQO1]), and cytotoxic bioactivities revealed that the estrogenicity of hops is a function of 8-PN, whereas their NQO1 induction and cytotoxic properties depend on XH levels. Antagonization of the estrogenicity of 8-PN by elevated XH concentrations provided evidence for the interdependence of the biological effects. A designed postmenopausal hop extract was prepared to balance 8-PN and XH levels for both estrogenic and chemopreventive properties. An extract designed for premenopausal women contains reduced 8-PN levels and high XH concentrations to minimize estrogenic while retaining chemopreventive properties. This study demonstrates the feasibility of modulating the concentrations of bioactive compounds in botanical extracts for potentially improved efficacy and safety.

Synergy and antagonism in natural product extracts: when 1 + 1 does not equal 2

“…The Pauli group recently demonstrated this possibility by producing specialized “knock-out” extracts of Humulus lupus L. (Cannabaceae) containing differential levels of biologically active constituents. 149 Depending on the ratio of active constituents, extracts showed either estrogenic or chemopreventive activity, illustrating that extracts can be designed for specific biological activities through modulating concentrations of bioactive constituents. With this approach, researchers identified certain extracts whose estrogenic activity was not explained by the expected contribution of the known active constituent 8-prenylnaringenin, suggesting that antagonistic or synergistic constituents may also be present in these extracts.…”

Flavonoids as Phytoestrogenic Components of Hops and Beer

“…Properly developed hops extract, i.e., containing a reduced level of estrogen 8-PN ( 4 ) and a higher concentration of chemopreventive XN ( 1 ), can be intended for women in premenopausal period. The extract intended for postmenopausal women would be slightly changed [ 115 ].…”

“…Not Intended to Diagnose, Treat, Cure or Prevent Any Disease.” 25 Years of Botanical Dietary Supplement Research and the Lessons Learned

“…From a research perspective, another novel technology that has recently come to light, which may facilitate the sorting through the myriad phytochemicals within an extract to find those select few that may have unique pharmacological or toxicological properties, is the “knock‐out” extract. This approach, pioneered by researchers at the University of Illinois‐Chicago's Center for Botanical Dietary Supplement Research and Center for Natural Product Technologies, provides a new means of uncovering contributions of individual phytoconstituents to the multifaceted biological effects of a botanical extract and uncovers interactions between them . Once individual pharmacological effects have been assigned to certain phytoconstituents, it becomes possible to design specialized extracts by removing (“knocking‐out”) compounds that impair desired bioactivity or produce adverse effects.…”

“…Countercurrent separation, which utilizes immiscible liquid−liquid two‐phase solvent systems as chromatographic phases, is the principal means by which these optimized extracts are prepared. As proof of concept, a “knock‐out” hops ( Humulus lupulus ) extract was prepared with countercurrent separation that minimized estrogenic properties while retaining chemopreventative properties . In the future, this approach may reduce interfering or unwanted bioactivities in botanical extracts, potentially leading to the production of BDS with increased efficacy and safety.…”

“…Despite inspections by the FDA and implementation of cGMPs, the purposeful adulteration of BDS with conventional medications and illicit drugs still plagues certain sectors of the DS industry . Weight‐loss DS, exercise performance enhancement DS (especially those marketed for body builders), and sexual performance enhancement DS are the three main categories most often vexed with adulterated products.…”