Modulation of CYP1A1 and CYP1A2 hepatic enzymes after oral administration of Chios mastic gum to male Wistar rats.

Efrosini S. Katsanou,Alexios-Leandros Skaltsounis,Christina Emmanouil,Kyriaki Machera,Nikolas Fokialakis,Katerina Kyriakopoulou,John Vontas

doi:10.1371/journal.pone.0100190

Efrosini S. Katsanou, Alexios-Leandros Skaltsounis + Show 5 more

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https://doi.org/10.1371/journal.pone.0100190

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Abstract

Chios mastic gum (CMG), a resin derived from Pistacia lentiscus var. chia, is known since ancient times for its pharmacological activities. CYP1A1 and CYP1A2 enzymes are among the most involved in the biotransformation of chemicals and the metabolic activation of pro-carcinogens. Previous studies referring to the modulation of these enzymes by CMG have revealed findings of unclear biological and toxicological significance. For this purpose, the modulation of CYP1A1 and CYP1A2 enzymes in the liver of male Wistar rats following oral administration of CMG extract (CMGE), at the levels of mRNA and CYP1A1 enzyme activity, was compared to respective enzyme modulation following oral administration of a well-known bioactive natural product, caffeine, as control compound known to involve hepatic enzymes in its metabolism. mRNA levels of Cyp1a1 and Cyp1a2 were measured by reverse transcription real-time polymerase chain reaction and their relative quantification was calculated. CYP1A1 enzyme induction was measured through the activity of ethoxyresorufin-O-deethylase (EROD). The results indicated that administration of CMGE at the recommended pharmaceutical dose does not induce significant transcriptional modulation of Cyp1a1/2 and subsequent enzyme activity induction of CYP1A1 while effects of the same order of magnitude were observed in the same test system following the administration of caffeine at the mean daily consumed levels. The outcome of this study further confirms the lack of any toxicological or biological significance of the specific findings on liver following the administration of CMGE.

Highlights

Chios mastic gum (CMG) is a resin derived from Pistacia lentiscus (L.) var. chia (Duham), Anacardiaceae, a plant which is mainly cultivated in southern part of Chios Island in Greece
CMG extract (CMGE) at both doses, failed to induce statistically significant transcriptional change in Cyp1a1 (p = 0.985 and 0.184, respectively) as compared to caffeine that increased significantly the transcription of Cyp1a1 when high dose was used (21.174-fold, p = 0.001). It seems that the low dose of caffeine, corresponding to the mean daily intake of caffeine received by an adult man, caused a transcriptional increase (2.286-fold) in the same order of magnitude as CMGE (1.289- and 3.538-fold for low and high dose, respectively)
With regard to Cyp1a2, medium and high doses of CMGE downregulated Cyp1a2 transcription (24.603- and 2 1.796-fold, respectively) but without a dose response albeit significantly only in the case of medium dose (p = 0.000), whilst the high dose of caffeine upregulated significantly Cyp1a2 mRNA (2.067-fold, p = 0.000). This result could mean that CMG acts as a ‘‘suicide’’ substrate for CYP1A2 and the consequence of down regulation of this isoform would mean the likelihood of several drug interactions when taken concomitantly with therapeutic drugs that are metabolized primarily by this CYP isoform

Summary

Introduction

CMG is a resin derived from Pistacia lentiscus (L.) var. chia (Duham), Anacardiaceae, a plant which is mainly cultivated in southern part of Chios Island in Greece. In the present study we sought to investigate whether CMG modulates transcriptional levels of Cyp1a1 and Cyp1a2 in rat liver following oral administration of CMG extract of the bioactive compounds, corresponding to the recommended daily consumption of CMG for pharmaceutical reasons and if the potential modulation is accompanied by changes in enzyme activity of CYP1A1.

Results

Conclusion