Modulation of Cytochrome P450 Metabolism and Transport across Intestinal Epithelial Barrier by Ginger Biophenolics

Abstract

Natural and complementary therapies in conjunction with mainstream cancer care are steadily gaining popularity. Ginger extract (GE) confers significant health-promoting benefits owing to complex additive and/or synergistic interactions between its bioactive constituents. Recently, we showed that preservation of natural “milieu” confers superior anticancer activity on GE over its constituent phytochemicals, 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G) and 6-shogaol (6S), through enterohepatic recirculation. Here we further evaluate and compare the effects of GE and its major bioactive constituents on cytochrome P450 (CYP) enzyme activity in human liver microsomes by monitoring metabolites of CYP-specific substrates using LC/MS/MS detection methods. Our data demonstrate that individual gingerols are potent inhibitors of CYP isozymes, whereas GE exhibits a much higher half-maximal inhibition value, indicating no possible herb-drug interactions. However, GE's inhibition of CYP1A2 and CYP2C8 reflects additive interactions among the constituents. In addition, studies performed to evaluate transporter-mediated intestinal efflux using Caco-2 cells revealed that GE and its phenolics are not substrates of P-glycoprotein (Pgp). Intriguingly, however, 10G and 6S were not detected in the receiver compartment, indicating possible biotransformation across the Caco-2 monolayer. These data strengthen the notion that an interplay of complex interactions among ginger phytochemicals when fed as whole extract dictates its bioactivity highlighting the importance of consuming whole foods over single agents. Our study substantiates the need for an in-depth analysis of hepatic biotransformation events and distribution profiles of GE and its active phenolics for the design of safe regimens.

The Carcinogenic Agent Diethylnitrosamine Induces Early Oxidative Stress, Inflammation and Proliferation in Rat Liver, Stomach and Colon: Protective Effect of Ginger Extract

“…Being one of the most frequently and heavily consumed natural dietary component, ginger and its polyphenolic compounds; zingerone, [6]-gingerol, and shogaol; have been reported for their chemoprotective and antioxidant effects in carcinogenesis (Chung et al, 2001;Mohd-Yusof et al, 2002;Manju and Nalini, 2005). Having more profound effect than gingerols, its active components, (Mukkavilli et al, 2014); researchers highlight the importance of utilizing entire ginger extract over its active components (Prasad and Tyagi, 2015b) with recently reported anti-oxidant, anti-inflammatory and anti-apoptotic effects of whole ginger rhizome extract in rat model of diabetic nephropathy (Al Hroob et al, 2018) Nitrosamines as dietary carcinogens are associated with the etiology of HCC and contribute to the development of oxidative stress, chronic inflammation, and cellular proliferation in response to tissue injury, leading to hepatocarcinogenesis (Darvesh and Bishayee, 2013).…”

Ginger and Its Constituents: Role in Prevention and Treatment of Gastrointestinal Cancer

“…Ginger ingredients have shown to modulate cytochrome P450 enzyme. The inhibition of CYP enzymes by ginger extract was more than its active components, gingerols [ 32 ]. Thus authors highlight the importance of consuming whole foods over active constituents.…”

Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation

“…Recent studies have reported their modulatory role in CYP450 systems, but only as individual plants. It was found that purified small molecules like 6- or 8-gingerols from ginger are much stronger inhibitors compared to whole ginger extracts [ 40 ]. In another study, cyclosporine bioavailability in animals went down only via oral delivery because ginger extracts blocked gastrointestinal mobility without any direct effect on CYP450 liver enzymes [ 41 , 42 ].…”