1-Aminobenzotriazole, cytochrome

Mechanism-based inactivation of cytochrome P450 2B1 by N-benzyl-1-aminobenzotriazole. Chemical Research in Toxicology, 10 (5), 600-608. 

Ortiz de Montellano, P.R. and Mathews, J.M. (1981) Autocatalytic alkylation of the cytochrome P-450 prosthetic haem group by 1-aminobenzotriazole. Isolation of an NN-bridged benzyne-protoporphyrin IX adduct. Biochemical Journal, 195 (3), 761-764. 

Figure 16 Mechanism of inhibition of the CYP enzyme inactivator ABT. Abbreviations CYP, cytochrome P450 ABT, 1-aminobenzotriazole.

Reichhart, D., Simon, A., Durst, F., Mathews, J.M., and Ortiz de Montellano, P.R., Autocatalytic inactivation of plant cytochrome P-450 enzymes selective inactivation of cinnamic acid 4-hydroxylase from Helianthus tuberosus by 1-aminobenzotriazole, Arch. Biochem. Biophys., 216, 522-529, 1982. 

As total inhibitors of the P450 enzyme family, 1-Aminobenzotriazole (Lee and Slattery 1997) and Proadifen (SKF525A) (Lee et al. 1998) are suitable to distinguish from non-cytochrome P450 mediated pathways. 

An inhibiting chemical slows the enzymatic metabolism of a toxic chemical. In this instance, if the uptaken chemical itself is the toxin, inhibition will slow the metabolism and intensify its action. If the metabolite of the absorbed xenobiotic is the toxic agent, inhibition will decrease the toxic affect. Vinyl chloride uptake in rats results in the lowering of cytochrome P450 and a corresponding loss of ability to metabolize other xenobiotics. Other inhibitors include diethyl maleate, which inhibits glutathione s-transferase and 1-aminobenzotriazole, which inhibits P450. 

Mathews, J.M. and J.R. Bend (1993). N-Aralkyl derivatives of 1-aminobenzotriazole as potent isozyme-selective mechanism-based inhibitors of rabbit pulmonary cytochrome P450 in vivo. J. Pharmacol. Exp. Then 265, 281—285. 

J.B. TarlofF(1992). 1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats. Fundam. Appl. Toxicol. 19, 43-49. 

S. Takemori, and H.D. Colby (1994). Inhibition of adrenal cytochromes P450 by 1-aminobenzotriazole in vitro. Selectivity for xenobiotic metabolism. BiocAew. Pharmacol. 48, 1421-1426. 

Colby, H.D., B. Abbott, M. Cachovic, K.M. Debolt, and B.A. Mico (1995). Inactivation of adrenal cytochromes P450 by 1-aminobenzotriazole. Divergence of in vivo and in vitro actions. Biochem. Pharmacol. 49, 1057-1062. 

Sinai, C.J. and J.R. Bend (1996). Kinetics and selectivity of mechanism-based inhibition of guinea pig hepatic and pulmonary cytochrome P450 by N-benzyl-1-aminobenzotriazole and N-alpha-methylbenzyl-1 -aminobenzotriazole. Drug Metab. Dispos. 24, 996-1001. 

F. Durst (1987). Effect of the cytochrome P-450 inactivator 1-aminobenzotriazole on the metabolism of chlortoluron and isoproturon in wheat. Pest. Biochem. Biophys. 28, 371-380. 

Capello, S., L. Henderson, F. DeGrazia, D. Liberato, W. Garland, and C. Town (1990). The effect of the cytochrome P-450 suicide inactivator, 1-aminobenzotriazole, on the in vivo metabolism and pharmacologic activity of flurazepam. Drug Metab. Dispos. 18, 190-196. 

Aminobenzotriazole and related triazoles, all of which are aryne precursors, are autocatalytic inactivators of cytochrome P-450 and related oxidases. Evidence has been presented that the enzyme oxidizes these substrates to benzyne which then binds covalently to the heme prosthetic group of the enzyme, possibly as in 120, thus deactivating it. 

B enzyne and Cyclobutadlene Stereoelectronlc Activation - The catalytic interaction of cytochrome P-450 with 1-aminobenzotriazole (2), a compound that releases benzyne when chemically oxidized, results in time-dependent enzyme inactivation. 2,63 An unusual prosthetic heme adduct is formed in which two vicinal nitrogens of protoporphyrin IX are bridged by an ortho-substituted phenyl ring. The Inactivation reaction occurs even when substituents are placed on the exocyclic amino group of 1-amlnobenzo-triazole, although enzyme inactivation by substituted analogues has not been well characterized. The catalytic role of the enzyme and the structure of the heme adduct indicate that inactivation follows oxidative release of benzyne or a benzyne-like species within the active site of the enzyme. 

Cinnamic Acid 4-Hvdroxvlase - The p-hydroxylation of cinnamic acid in the biosynthesis of lignins by plants is mediated by a cytochrome P-450 enz3nne.l ° The cinnamic acid 4-hydroxylase of Jerusalem artichoke tubers is preferentially inactivated by 1-aminobenzotriazole in a tlme-and catalysis-dependent manner.The specific inhibition of cytochrome P-450 enzymes in plants provides a possible avenue for the design of new classes of herbicides and other crop-protection agents. 

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