Modulation of Metabolic Enzymes by Dietary Phytochemicals: A Review of Mechanisms Underlying Beneficial Versus Unfavorable Effects
Sandhya Mandlekar, Jin-Liern Hong and Ah-Ng Tony Kong
Affiliation: Department of Drug Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey.
Keywords: Dietary Phytochemicals, herbs, natural products, drug metabolizing enzymes, drug transporters, diet-drug pharmacokinetic interactions, cancer chemoprevention
In this review, we extensively survey the literature documenting the interaction of herbal components of the diet with metabolic enzymes. These interactions are mediated by the phytochemicals contained in herbs and can mechanistically occur at both transcriptional or post-transcriptional level. At the transcriptional level, dietary phytochemicals can cause induction of drug metabolizing enzymes (DMEs: phase I and phase II) and transporters via nuclear hormone receptors, including the pregnane X receptor (PXR), the constitutive androstane receptor (CAR) or the aryl hydrocarbon receptor (AHR), as well as non-hormonal receptors, including the nuclear factor erythroid-derived 2 (NRF2) transcription factor. Herbs can also modulate the activity of DMEs and transporters by competitive binding to or inactivation of the protein. There are cases where herbal constituents can undergo DME-mediated bioactivation resulting in DNA adduct formation and toxicity. The consequences of herb-DME interactions can be a) beneficial effects, such as cancer prevention, b) undesirable effects, such as pharmacokinetic interactions with co-administered drugs, c) harmful effects, such as organ toxicity or carcinogenesis. The molecular, cellular, and physiological mechanisms of herb-DME interactions will be discussed with examples of in vitro, animal or clinical studies of phytochemicals and in the context of human health benefits or risks.
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