title: Enterohepatic recirculation of bioactive ginger phytochemicals is associated with enhanced tumor growth-inhibitory activity of ginger extract.
abstract: Phytochemical complexity of plant foods confers health-promoting benefits including chemopreventive and anticancer effects. Isolating single constituents from complex foods may render them inactive, emphasizing the importance of preserving the natural composition of whole extracts. Recently, we demonstrated in vitro synergy among the most abundant bioactive constituents of ginger extract (GE), viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G) and 6-shogaol (6S). However, no study has yet examined the in vivo collaboration among ginger phytochemicals or evaluated the importance, if any, of the natural 'milieu' preserved in whole extract. Here, we comparatively evaluated in vivo efficacy of GE with an artificial quasi-mixture (Mix) formulated by combining four most active ginger constituents at concentrations equivalent to those present in whole extract. Orally fed GE showed 2.4-fold higher tumor growth-inhibitory efficacy than Mix in human prostate tumor xenografts. Pharmacokinetic evaluations and bioavailability measurements addressed the efficacy differences between GE and Mix. Plasma concentration-time profiles revealed multiple peaking phenomenon for ginger constituents when they were fed as GE as opposed to Mix, indicating enterohepatic recirculation. Bioavailability of 6G, 8G, 10G and 6S was 1.6-, 1.1-, 2.5- and 3.4-fold higher, respectively, when dosed with GE compared with Mix. In addition, gingerol glucuronides were detected in feces upon intravenous administration confirming hepatobiliary elimination. These data ascribe the superior in vivo efficacy of GE to higher area under the concentration time curves, greater residence time and enhanced bioavailability, of ginger phytochemicals, when fed as a natural extract compared with artificial Mix, emphasizing the usefulness of consuming whole foods over single agents.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA, Advinus Therapeutics, Bangalore, Karnataka 560058, India, Department of Chemistry, University of Delhi, Delhi 110007, India and Department of Biomedical Engineering, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Sushma R
authors.initials: SR
authors.lastname: Gundala
authors.affiliation: Advinus Therapeutics, Bangalore, Karnataka 560058, India.
authors.forename: Rao
authors.initials: R
authors.lastname: Mukkavilli
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA, Advinus Therapeutics, Bangalore, Karnataka 560058, India, Department of Chemistry, University of Delhi, Delhi 110007, India and Department of Biomedical Engineering, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India and.
authors.forename: Pooja
authors.initials: P
authors.lastname: Yadav
authors.affiliation: Department of Chemistry, University of Delhi, Delhi 110007, India and.
authors.forename: Vibha
authors.initials: V
authors.lastname: Tandon
authors.affiliation: Advinus Therapeutics, Bangalore, Karnataka 560058, India.
authors.forename: Subrahmanyam
authors.initials: S
authors.lastname: Vangala
authors.affiliation: Department of Biomedical Engineering, McGill University, Montreal, Quebec H3G 1Y6, Canada.
authors.forename: Satya
authors.initials: S
authors.lastname: Prakash
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA 30303, USA, Advinus Therapeutics, Bangalore, Karnataka 560058, India, Department of Chemistry, University of Delhi, Delhi 110007, India and Department of Biomedical Engineering, McGill University, Montreal, Quebec H3G 1Y6, Canada raneja@gsu.edu.
authors.forename: Ritu
authors.initials: R
authors.lastname: Aneja
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D002396:Catechols / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004764:Enterohepatic Circulation; D005233:Fatty Alcohols / Q000737:chemistry / Q000378:metabolism; D020939:Zingiber officinale / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D010636:Phenols / Q000737:chemistry; D064209:Phytochemicals / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D010936:Plant Extracts / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002396:Catechols; D005233:Fatty Alcohols; D010636:Phenols; D064209:Phytochemicals; D010936:Plant Extracts; C007845:gingerol