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First published on September 22, 2006; DOI: 10.1124/dmd.106.011452

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Received for publication June 20, 2006.
Revised September 20, 2006.
Accepted for publication September 20, 2006.

Structure-Activity Relationship and Elucidation of the Determinant Factor(s) Responsible for the Mechanism-Based Inactivation of P450 2B6 by Substituted Phenyl Diaziridines

Yoshimasa Kobayashi 1, Chitra Sridar 1, Ute M Kent 1, Satish G Puppali 2, John M Rimoldi 2, Haoming Zhang 1, Lucy Waskell 1, Paul F. Hollenberg 3*

1 University of Michigan 2 University of Mississippi 3 University of Michigan School of Medicine

* Address correspondence to: E-mail: phollen{at}umich.edu

Abstract

It has been previously demonstrated that several 3-trifluoromethyl-3-(4-alkoxyphenyl) diaziridines inhibit the 7-ethoxy-4-(trifluoroethyl)coumarin (7-EFC) O-deethylation activity of P450 2B6 in a mechanism-based manner. In contrast, 3-trifluoromethyl-3-((4-methylthio)phenyl) diaziridine did not have any effect on the activity of P450 2B6. Interestingly, both the alkoxy and the thiophenyl compounds were metabolized by P450 2B6. In this report, the structure-activity relationships (SAR) for the mechanism-based inactivation of cytochrome P450 2B6 by a series of aryl diaziridines were investigated. Three diaziridines that did not contain a 4-alkoxy- substituent on their phenyl ring, namely, 3-trifluoromethyl-3-(3-methoxyphenyl)diaziridine, 3-trifluoromethyl-3-phenyl diaziridine and, 3-trifluoromethyl-3-(4-chlorophenyl)diaziridine had no effect on the P450 2B6 7-EFC activity. Another analog that did not contain a diaziridine substructure, 3-trifluoromethyl-3-(4-methoxyphenyl)ethanone, also had no effect on the activity of P450 2B6. Glutathione ethylester adducts of the phenyldiaziridine reactive intermediates were isolated from reaction mixtures of the inactivated samples and analyzed by LC-MS/MS. The structures of the conjugates suggested that the electrophilic reactive intermediate in each case was a quinone methide (quinomethane), 4-ethylidene-cyclohexa-2,5-dienone, generated from the 4-alkoxyphenyldiaziridines by removal of both of the diaziridine and the 4-alkyl groups. In conclusion, the determinant factor for the mechanism-based inactivator activity of the aryl diaziridines seems to be the formation of the reactive quinomethane intermediate, which is generated from the 4-alkoxyphenyl diaziridines by a P450-catalyzed metabolic reaction.


Key words: CYP2B, GC/MS, glutathione conjugates, mechanism-based inhibition, monooxygenases, NADPH cytochrome P450 reductase




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