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

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 K-I 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.

Automated summary

Synthetic analogues of 19-HETE show inhibitory effects on CYP1A1 and CYP1B1 activity through a noncompetitive mechanism, with no significant impact on CYP1A2. These analogues can effectively inhibit EROD and MROD activities in cell-based assays and human liver microsomes, presenting a potential novel therapeutic approach for cancer and cardiovascular diseases.