Limits...
Interactions between CYP3A4 and Dietary Polyphenols.

Basheer L, Kerem Z - Oxid Med Cell Longev (2015)

Bottom Line: Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs.Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4.Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, 76100 Rehovot, Israel.

ABSTRACT
The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols.

No MeSH data available.


Related in: MedlinePlus

The catalytic cycle of P450s: a flavonoid structure was selected to represent dietary polyphenols.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4477257&req=5

fig1: The catalytic cycle of P450s: a flavonoid structure was selected to represent dietary polyphenols.

Mentions: The active site of a substrate-free cytochrome P450 contains one-heme iron center anchored by the four bonds of the heme group, fifth proximal ligand of the conserved cysteine, and water molecule as the sixth distal ligand [1]. The catalytic mechanisms of P450 enzymes are thoroughly investigated in the literature, as demonstrated in a scheme based on previous publications (Figure 1) [1, 40–42]. Like most other P450 enzymes, CYP3A4 acts as a monooxygenase (e.g., it catalyzes the insertion of one atom of oxygen into an organic substrate while another oxygen atom is reduced to water) [43]. The substrate chemical characteristics and the preferred position of hydroxyl insertion change from one family of P450 to another [3, 44–46]. P450 enzymes play a major role in phase I metabolism of dietary xenobiotics, including polyphenols, whereby a hydroxyl group is introduced to the molecule. These metabolic products are more water-soluble and become available to phase II enzymes. The latter include UDP-glucuronosyl transferases and sulfotransferases that add to the increased water solubility of the hydroxylated polyphenols, producing glucuronides and sulfates, which are then eliminated from the body [29, 47, 48].


Interactions between CYP3A4 and Dietary Polyphenols.

Basheer L, Kerem Z - Oxid Med Cell Longev (2015)

The catalytic cycle of P450s: a flavonoid structure was selected to represent dietary polyphenols.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4477257&req=5

fig1: The catalytic cycle of P450s: a flavonoid structure was selected to represent dietary polyphenols.
Mentions: The active site of a substrate-free cytochrome P450 contains one-heme iron center anchored by the four bonds of the heme group, fifth proximal ligand of the conserved cysteine, and water molecule as the sixth distal ligand [1]. The catalytic mechanisms of P450 enzymes are thoroughly investigated in the literature, as demonstrated in a scheme based on previous publications (Figure 1) [1, 40–42]. Like most other P450 enzymes, CYP3A4 acts as a monooxygenase (e.g., it catalyzes the insertion of one atom of oxygen into an organic substrate while another oxygen atom is reduced to water) [43]. The substrate chemical characteristics and the preferred position of hydroxyl insertion change from one family of P450 to another [3, 44–46]. P450 enzymes play a major role in phase I metabolism of dietary xenobiotics, including polyphenols, whereby a hydroxyl group is introduced to the molecule. These metabolic products are more water-soluble and become available to phase II enzymes. The latter include UDP-glucuronosyl transferases and sulfotransferases that add to the increased water solubility of the hydroxylated polyphenols, producing glucuronides and sulfates, which are then eliminated from the body [29, 47, 48].

Bottom Line: Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs.Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4.Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, P.O. Box 12, 76100 Rehovot, Israel.

ABSTRACT
The human cytochrome P450 enzymes (P450s) catalyze oxidative reactions of a broad spectrum of substrates and play a critical role in the metabolism of xenobiotics, such as drugs and dietary compounds. CYP3A4 is known to be the main enzyme involved in the metabolism of drugs and most other xenobiotics. Dietary compounds, of which polyphenolics are the most studied, have been shown to interact with CYP3A4 and alter its expression and activity. Traditionally, the liver was considered the prime site of CYP3A-mediated first-pass metabolic extraction, but in vitro and in vivo studies now suggest that the small intestine can be of equal or even greater importance for the metabolism of polyphenolics and drugs. Recent studies have pointed to the role of gut microbiota in the metabolic fate of polyphenolics in human, suggesting their involvement in the complex interactions between dietary polyphenols and CYP3A4. Last but not least, all the above suggests that coadministration of drugs and foods that are rich in polyphenols is expected to stimulate undesirable clinical consequences. This review focuses on interactions between dietary polyphenols and CYP3A4 as they relate to structural considerations, food-drug interactions, and potential negative consequences of interactions between CYP3A4 and polyphenols.

No MeSH data available.


Related in: MedlinePlus