Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches
Abstract
:1. Introduction
2. Cytosolic NAD(P)H:Quinone Oxidoreductase (NQO1) and Microsomal Cytochrome P450 (CYP) 1A1 and 1A2 Enzymes Reductively Activate 3-NBA and AAI
2.1. Reductive Activation of 3-NBA and Aristolochic Acid I (AAI) by Human NQO1
2.2. Participation of Conjugation Enzymes in Activation of 3-NBA and AAI
Enzymatic System | Total Levels of DNA Adducts in RAL a (Mean ± SD/108 Nucleotides) | |
---|---|---|
3-NBA | AAI | |
NQO1 + NADPH | 10 ± 2 | 15 ± 2 |
NQO1 + NADPH + dicoumarol | 0.1 ± 0.01 | 0.4 ± 0.04 |
NQO1 + NADPH + SULT1A1 + PAPS b | 16 ± 2 | 15 ± 2 |
NQO1 + NADPH + SULT1A2 + PAPS | 36 ± 2 | 16 ± 2 |
NQO1 + NADPH + NAT1 + acetyl-CoA c | 16 ± 2 | 15 ± 2 |
NQO1 + NADPH + NAT2 + acetyl-CoA | 1720 ± 50 | 17 ± 2 |
2.3. Reductive Activation of 3-NBA and AAI by Human CYP1A1 and 1A2
Enzymatic System | Total Levels of DNA Adducts in RAL a (Mean ± SD/108 Nucleotides) | |
---|---|---|
3-NBA | AAI | |
POR + NADPH | 10 ± 2 | 15 ± 2 |
CYP1A1 + POR + NADPH | 52 ± 5 | 84 ± 7 |
CYP1A2 + POR + NADPH | 48 ± 5 | 126 ± 12 |
CYP1B1 + POR + NADPH | 5 ± 1 | 11 ± 1 |
3. Calculation of 3-NBA and AAI Reduction, Heterolytic Cleavage of 3-NBA and AAI N-Hydroxyl Derivatives and Their Sulfate or Acetate Conjugates—Thermodynamic Approaches
(A) | [kcal/mol] a | |||||
Reaction step (Figure 1) solvation model | 1. | 2. | 3a. | 3b. | 3c. | 4. |
NO2 → NO | NO → NHOH | NHOH → NH+ + OH− | NHOAc → NH+ + Ac− | NHOSO3− → NH+ + SO42− | NHOH → NH2 | |
CPCM | −46.9 | −28.3 | 22.3 | −6.1 | −8.3 | −64.5 |
LD | −44.0 | −27.0 | −4.5 | −22.3 | −24.8 | −67.7 |
(B) | [kcal/mol] a | |||||
Reaction step (Figure 3) solvation model | 1. | 2 + 3. | 4a. | 4b. | 4c. | 5. |
NO2 → NO | NO → N-OH-lact + OH− | N-OH-lact → N-lact+ + OH− | N-OAc-lact → N-lact+ + Ac− | N-OSO3−-lact → N-lact+ + SO42− | N-OH-lact → N-lact + H2O | |
CPCM | −46.7 | −19.1 | 30.6 | 0.6 | −4.9 | −70.7 |
LD | −40.4 | −9.1 | −7.1 | −29.4 | −24.6 | −69.8 |
4. Binding of 3-NBA and AAI to the Active Sites of NQO1 and CYP1A1/2 Enzymes
4.1. Binding of 3-NBA and AAI to the Active Site of NQO1
NQO1 FADH− Deprotonated (Anionic Form) | NQO1 Enol-FADH2 (Protonated Form) | |||||
---|---|---|---|---|---|---|
direct H-transfer | direct H-transfer | mediated H-transfer (e−,H+,e−) | ||||
Estimated Free Energy of binding [kcal/mol] | N5(FAD)-O(NBA/AAI) distance [Å] a | Estimated Free Energy of binding [kcal/mol] | N5(FAD)-O(NBA/AAI) distance [Å] a | Estimated Free Energy of binding [kcal/mol] | OH(Y128)-O(NBA/AAI) distance [Å] b | |
3-NBA | −5.7 | 3.7 | −5.7 | 3.5 | −6.2 | 3.1 |
AAI | −6.4 | 3.2 | −6.3 | 3.2 | −7.9 | 2.8 |
4.2. Binding of 3-NBA and AAI to the Active Sites of CYP1A1 and 1A2
CYP1A1 | CYP1A2 | CYP1B1 | ||||
---|---|---|---|---|---|---|
Estimated Free Energy of binding [kcal/mol] | 3-NBA/AAI—heme distance [Å] a | Estimated Free Energy of binding [kcal/mol] | 3-NBA/AAI—heme distance [Å] a | Estimated Free Energy of binding [kcal/mol] | 3-NBA/AAI—heme distance [Å] a | |
3-NBA | −8.04 | 4.2 | −8.02 | 4.5 | −7.73 | 4.7 |
AAI | −5.66 | 3.9 | −5.81 | 3.2 | −5.59 | 3.0 |
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Stiborová, M.; Frei, E.; Schmeiser, H.H.; Arlt, V.M.; Martínek, V. Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches. Int. J. Mol. Sci. 2014, 15, 10271-10295. https://doi.org/10.3390/ijms150610271
Stiborová M, Frei E, Schmeiser HH, Arlt VM, Martínek V. Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches. International Journal of Molecular Sciences. 2014; 15(6):10271-10295. https://doi.org/10.3390/ijms150610271
Chicago/Turabian StyleStiborová, Marie, Eva Frei, Heinz H. Schmeiser, Volker M. Arlt, and Václav Martínek. 2014. "Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches" International Journal of Molecular Sciences 15, no. 6: 10271-10295. https://doi.org/10.3390/ijms150610271