title: How is a metabolic intermediate formed in the mechanism-based inactivation of cytochrome P450 by using 1,1-dimethylhydrazine: hydrogen abstraction or nitrogen oxidation?
abstract: A precise understanding of the mechanism-based inactivation of cytochrome P450 enzymes (P450s) at the quantum mechanical level should allow more reliable predictions of drug-drug interactions than those currently available. Hydrazines are among the molecules that act as mechanism-based inactivators to terminate the function of P450s, which are essential heme enzymes responsible for drug metabolism in the human body. Despite its importance, the mechanism explaining how a metabolic intermediate (MI) is formed from hydrazine is not fully understood. We used density functional theory (DFT) calculations to compare four possible mechanisms underlying the reaction between 1,1-dimethylhydrazine (or unsymmetrical dimethylhydrazine, UDMH) and the reactive compound I (Cpd I) intermediate of P450. Our DFT calculations provided a clear view on how an aminonitrene-type MI is formed from UDMH. In the most favorable pathway, hydrogen is spontaneously abstracted from the N2 atom of UDMH by Cpd I, followed by a second hydrogen abstraction from the N2 atom by Cpd II. Nitrogen oxidation of nitrogen atoms and hydrogen abstraction from the C-H bond of the methyl group were found to be less favorable than the hydrogen abstraction from the N-H bond. We also found that the reaction of protonated UDMH with Cpd I is rather sluggish. The aminonitrene-type MI binds to the ferric heme more strongly than a water molecule. This is consistent with the notion that the catalytic cycle of P450 is impeded when such an MI is produced through the P450-catalyzed reaction.
authors.affiliation: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371. hirao@ntu.edu.sg
authors.forename: Hajime
authors.initials: H
authors.lastname: Hirao
authors.forename: Pratanphorn
authors.initials: P
authors.lastname: Chuanprasit
authors.forename: Ying Yi
authors.initials: YY
authors.lastname: Cheong
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wang
mesh_terms: D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D004127:Dimethylhydrazines / Q000737:chemistry*; D006418:Heme / Q000737:chemistry* / Q000378:metabolism*; D006859:Hydrogen; D006860:Hydrogen Bonding; D009584:Nitrogen / Q000737:chemistry*; D010084:Oxidation-Reduction; D011789:Quantum Theory; D014867:Water / Q000737:chemistry
chemical_list: D004127:Dimethylhydrazines; D014867:Water; D006418:Heme; C013958:dimazine; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System; D009584:Nitrogen