Program

PO4-9-9

Antimutagenic effect of grapefruit juice compounds against 2-aminoanthracene activation by human and rat cytochrome P4501A1

[Speaker] Rebeca Santes-Palacios:1
[Co-author] Rafael Camacho-Carranza:1, Jesus Javier Espinosa-Aguirre:1
1:Genomic Medicine and Environmental Toxicology, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Mexico

One of the most important enzymes participating in procarcinogen activation is Cytochrome P4501A1 (CYP1A1). Using different experimental models, the inhibition of its catalytic activity has been proposed as a strategy for the search of potential chemopreventive compounds. However, there are only a few CYP inhibitors in the clinical phase.
One of the main problem using the above mentioned strategy, could be the assumption that compounds interact with the human enzyme in the same way as with other species' enzyme. So, we focused on the study of the interspecies differences in interaction of mutagens and inhibitors with human and rat CYP1A1 using similar experimental conditions.
We analyzed through an in silico methodology, the binding of three mutagens (benzo(a)pyrene, BaP; 7, 12-dimethylbenzoanthracene, DMBA; 2-aminoanthracene, 2-AA) and three inhibitors (alpha-naphtoflavone, ANF; naringenin, NAR; bergamottin, BG) to human and rat CYP1A1 catalytic site. The molecular docking assay suggests a greater affinity of mutagens for human CYP1A1 but a higher energetically favorable binding of the inhibitors with rat enzyme.
We also evaluated the differences on 2-AA activation by CYP1A1 through Ames test. Mutagenic potency was calculated resulting in 7.3 revertants per ng of 2-AA with rat CYP1A1 and 22.9 revertants per ng of 2-AA with human enzyme). Rat CYP1A1 is approximately 3-fold less efficient to activate 2-AA than human CYP1A1.
On the other hand, the antimutagenic effect of NAR and BG against 2-AA activation mediated by rat CYP1A1 is 60 and 44-fold respectively higher than with human enzyme.
In conclusion, there are differences in the interaction of grapefruit compounds and 2-AA with human and rat CYP1A1. There is correlation between in silico and in vitro data, human enzyme is more sensitive to the effect of mutagens, whereas the rat enzyme is more sensitive to the inhibitors. These data are useful to improve the interpolation of results obtained with animal models to other species.

Acknowledgements: This work was partially supported by DGAPA-PAPIIT IN206915 and IN204117. Technical assistance of Sandra Luz Hernandez Ojeda is appreciated.

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