Pharmacogenetics, Pharmacogenomics and Epigenetics of Nrf2-regulated Xenobioticmetabolizing Enzymes and Transporters by Dietary Phytochemical and Cancer Chemoprevention
2013
Cancer chemopreventive activities of various phytochemicals have been attributed to the modulation of xenobiotic disposition,
which includes absorption, distribution, metabolism, and excretion. The interaction between xenobiotics and xenobiotic-metabolizing enzymes
(XMEs) is bidirectional. XMEs are responsible for the biotransformation of xenobiotics such as bioactivation and detoxification.
Conversely, xenobiotics affect XMEs through transcriptional regulation (induction or suppression) and post-translational interactions (inhibition
or activation). Similar relationships also exist between xenobiotics and their transporters. Studies conducted over the past decade
have demonstrated that the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), plays a critical role in the regulation of
detoxifying enzymes and transporters through a signaling system that senses and responds to redox imbalance. The role of Nrf2 in the interaction
between chemopreventive phytochemicals and detoxifying enzymes/transporters has become an important topic in cancer chemoprevention.
In this review, the genetic and epigenetic factors that contribute to Nrf2-mediated regulation of detoxifying XMEs and
transporters are discussed in the context of cancer chemoprevention. Phytochemicals may modulate the genome as well as epigenome, altering
the regulation of XMEs and transporters, which may be critical for both cancer chemoprevention and the prevention of other oxidative
stress- and inflammatory-related diseases, including cardiovascular, metabolic and neurological pathologies. The pharmacogenomic
expression of XMEs and transporters, with an emphasis on both genomics and epigenetics, will also be discussed.
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