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Novel Synthetic Analogues of 19(S/R)-Hydroxyeicosatetraenoic Acid Exhibit Noncompetitive Inhibitory Effect on the Activity of Cytochrome P450 1A1 and 1B1

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objectives

Cytochrome P450 (CYP) 1A1 and CYP1B1 enzymes play a significant role in the pathogenesis of cancer and cardiovascular diseases (CVD) such as cardiac hypertrophy and heart failure. Previously, we have demonstrated that R- and S-enantiomers of 19-hydroxyeicosatetraenoic acid (19-HETE), an arachidonic acid endogenous metabolite, enantioselectively inhibit CYP1B1. The current study was conducted to test the possible inhibitory effect of novel synthetic analogues of R- and S-enantiomers of 19-HETE on the activity of CYP1A1, CYP1A2, and CYP1B1.

Methods

The O-dealkylation rate of 7-ethoxyresorufin (EROD) by recombinant human CYP1A1 and CYP1B1, in addition to the O-dealkylation rate of 7-methoxyresorufin (MROD) by recombinant human CYP1A2, were measured in the absence and presence of varying concentrations (0–40 nM) of the synthetic analogues of 19(R)- and 19(S)-HETE. Also, the possible inhibitory effect of both analogues on the catalytic activity of EROD and MROD, using RL-14 cells and human liver microsomes, was assessed.

Results

The results showed that both synthetic analogues of 19(R)- and 19(S)-HETE exhibited direct inhibitory effects on the activity of CYP1A1 and CYP1B1, while they had no significant effect on CYP1A2 activity. Nonlinear regression analysis and comparisons showed that the mode of inhibition for both analogues is noncompetitive inhibition of CYP1A1 and CYP1B1 enzymes. Also, nonlinear regression analysis and Dixon plots showed that the R- and S-analogues have KI values of 15.7 ± 4.4 and 6.1 ± 1.5 nM for CYP1A1 and 26.1 ± 2.9 and 9.1 ± 1.8 nM for CYP1B1, respectively. Moreover, both analogues were able to inhibit EROD and MROD activities in a cell-based assay and human liver microsomes.

Conclusions

Therefore, the synthetic analogues of 19-HETE could be considered as a novel therapeutic approach in the treatment of cancer and CVD.

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Authors and Affiliations

  1. Faculty of Pharmacy and Pharmaceutical Sciences, 2142J Katz Group-Rexall Centre for Pharmacy and Health Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada

    Sherif M. Shoieb & Ayman O. S. El-Kadi

  2. Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX, USA

    Rambabu Dakarapu & John R. Falck

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  1. Sherif M. Shoieb
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  2. Rambabu Dakarapu
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  3. John R. Falck
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  4. Ayman O. S. El-Kadi
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Correspondence to Ayman O. S. El-Kadi.

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Funding

This work was supported by a grant from the Canadian Institutes of Health Research [CIHR PS 168846] to A.O.S.E. S.M.S. is the recipient of Alberta Innovates Graduate Student Scholarship and Alberta Graduate Excellence Scholarship. JRF was supported by the Robert A. Welch foundation (I-0011).

Conflict of interest

Sherif M. Shoieb, Rambabu Dakarapu, John R. Falck and Ayman O.S. El-Kadi declare that they have no conflict of interest.

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Participated in research design: SMS, JRF and AOSE-K. Conducted experiments: SMS and RD. Performed data analysis: SMS and AOSE-K. Wrote or contributed to the writing of the manuscript: SMS, JRF and AOSE-K.

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Shoieb, S.M., Dakarapu, R., Falck, J.R. et al. Novel Synthetic Analogues of 19(S/R)-Hydroxyeicosatetraenoic Acid Exhibit Noncompetitive Inhibitory Effect on the Activity of Cytochrome P450 1A1 and 1B1. Eur J Drug Metab Pharmacokinet 46, 613–624 (2021). https://doi.org/10.1007/s13318-021-00699-9

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