The mechanism of microsomal azoreduction: predictions based on electronic aspects of structure-activity relationships.
The mechanism of microsomal azoreductase is regulated by the overall Hammett sigma substituent values on each ring. A substrate dye must exhibit an overall Hammett sigma substituent value either equal or more negative than -0.37 on either ring. Dyes with Hammett sigma substituent constants less negative than -0.37 will not be reduced by microsomal cytochrome P450. Microsomal reduction of azo dyes containing only electron-donating substituents on either ring is insensitive to both oxygen and carbon monoxide. The required Hammett sigma substituent value on the opposite benzene (prime) ring for I-substrates is therefore, sigma' P < or = 0. Reduction of azo dyes containing electron-withdrawing group on opposite (prime) is sensitive to both oxygen and carbon monoxide. The required Hammett sigma substituent value on the opposite benzene (prime) ring for S-substrates is, consequently, sigma' P > 0 (Table 3). Redox Potentials. Anaerobic cyclic voltammograms of azobenzene derivatives verify the following points: A nonsubstrate azo dye will not exhibit a positive potential. (Several nonsubstrate hydrazobenzenes exhibited positive potentials, but in a low range 0.41-0.48 V. Consequently, cyclic voltammetry can distinguish between nonsubstrate azobenzenes and their nonsubstrate half-reduced hydrazo analogs.) A substrate azo dye will exhibit a positive potential in the range +1.00 to +1.50 V. I-substrate: Both negative potentials are stable in air. S-substrate: The first negative potential will immediately quench upon exposure to air. I-substrates exhibit on average potentials which are approximately 0.6 V more negative than those for S-substrates. A comparison between the oxidative and the reductive pathway of microsomal cytochrome P450 indicates a similarity in the first two steps in the reaction cycle, for example, substrate binding and uptake of the first electron by the cytochrome [76, 109, 110]. Upon reduction of the iron, ferrous cytochrome P450 may bind oxygen or carbon monoxide in a competitive manner in the oxidative cycle or may directly transfer the electrons to the substrate in a stepwise fashion in the reductive cycle [76]. Estabrook et al. [111] suggested that carbon monoxide insensitivity can occur when the formation of ferrous cytochrome P450 substrate complex is rate limiting for the overall reaction. Structure-activity relationships of azo compounds depend on (1) the electron transport component and (2) the oxidation-reduction potential of the dye, which determines its ability to accept electrons from cytochrome P-450. Nesnow et al. examined a group of 36 aryl azo dyes for their ability to be reduced by rat liver microsomal azoreductase.(ABSTRACT TRUNCATED AT 400 WORDS)
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Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, New Jersey 07033-0539, USA.
D000818:Animals; D004579:Electron Transport; D006801:Humans; D008861:Microsomes / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009601:Nitroreductases; D010084:Oxidation-Reduction; D011237:Predictive Value of Tests; D051381:Rats; D013329:Structure-Activity Relationship
D009247:NADH, NADPH Oxidoreductases; D009601:Nitroreductases; C021106:azoreductase