1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology

Abstract

1-Aminobenzotriazole (1-ABT) is a pan-specific, mechanism-based inactivator of the xenobiotic metabolizing forms of cytochrome P450 in animals, plants, insects, and microorganisms. It has been widely used to investigate the biological roles of cytochrome P450 enzymes, their participation in the metabolism of both endobiotics and xenobiotics, and their contributions to the metabolism-dependent toxicity of drugs and chemicals. This review is a comprehensive evaluation of the chemistry, discovery, and use of 1-aminobenzotriazole in these contexts from its introduction in 1981 to the present.

Keywords: 1-Aminobenzotriazole; Arachidonic acid oxidation; Benzyne; Cytochrome P450; Drug metabolism; Estradiol; Heme adducts; Mechanism-based inhibition; Xenobiotics.

Figure 1:

Oxidation of 1-ABT (compound 1) produces benzyne, which can be chemically trapped to give 1,2,3,4-tetraphenylnaphthalene.

Figure 2:

Heme adduct formed by reaction of the heme of cytochrome P450 with autocatalytically activated 1-ABT. The peripheral substituents on the porphyrin are only shown schematically, as isomeric structures that differ in the pattern of peripheral substitution are possible.

Figure 3:

Two possible mechanisms for the P450-catalyzed oxidation of 1-ABT to benzyne, where [Por⁺.Fe(IV)=O] stands for the activated iron oxo species of cytochrome P450.

Figure 4:

Metabolites of 1-ABT formed in vivo in rats.

Figure 5:

Possible mechanism for the P450-catalyzed conversion of 1-ABT to benzotriazole.

Figure 6:

Analogues of 1-ABT with variants of the core 1-aminobenzotriazole structure are not effective mechanism-based inactivating agents.

Figure 7:

A possible mechanism for the formation of a nitroso compound that could coordinate to the heme iron of P450, resulting in observation of MI complexes. The reaction scheme shown is a modified version of that proposed by Sinal and Bend [90]. The R stands for H, Me, or Et, depending on whether it refers to experiments with compound 13, 14, or 15 (Table 2), respectively.

Figure 8:

Metabolites of thiazopyr and GNE-892 produced by cytochrome P450.

Figure 9:

Cytochrome P450 catalyzed oxidation resulting in a reduced metabolite.

Figure 10:

Metabolites of nevirapine formed by cytochrome P450 enzymes.

Figure 11:

The cytochrome P450-catalyzed transformation of tienilic acid to a glutathione conjugate is inhibited by 1-ABT.

Figure 12:

The hepatic metabolism of desloratadine elucidated with the help of 1-ABT.

Figure 13:

Epoxidation of precocene.

Figure 14:

Oxidation of 3-methylindole to a reactive methylene iminium product that alkylates proteins.

Figure 15:

Oxidation of cinnamic acid by cinnamic acid 4-hydroxylase in the biosynthesis of phenylpropanoids in plants.

Figure 16:

Structure of schisandrin B.

Figure 17:

Formation of 9,12,13-trihydroxy-10(E)-octadecenoic acid in Solanum lypoersicum (tomato).

Figure 18:

Pathways for the biosynthesis of hüorhammericine from tabersonine in the biogenesis of vindoline.

Figure 19:

Structures of some of the herbicide agents whose metabolism is shown by studies with 1-ABT to involve cytochrome P450 enzymes.

Figure 20:

Two intermediates in the biosynthesis of enokipodin A, B, C, and D identified as a result of inhibition of P450 enzymes by 1-ABT. The two intermediates are shown in the boxes.