title: Hepatic microsomal azoreductase activity. Reactivity of azo dye substrates is determined by their electron densities and redox potentials.
abstract: We have previously established that microsomal reduction of azo dyes requires polar electron-donating ring substituents [e.g. -OH, -NH2, -NHCH3, or -N(CH3)2]. Reduction of dyes substituted exclusively with such moieties on either phenyl ring is insensitive to both O2 and CO (I-substrates). In contrast, azoreduction of compounds containing additional electron-withdrawing substituents (e.g. -SO3H, -COOH, -COOCH3, and -AsO3H2) on the opposite (prime) phenyl ring is sensitive to both O2 and CO (S-substrates). We have recently shown that Hammett aromatic substituent constants and redox potentials of the dyes, determined by cyclic voltammetry (CV), distinguish between I- and S-substrates. Dyes that exhibit positive Hammett sigma substituent constants on 1 of the 2 rings are S-substrates, and undergo immediate quenching of their one electron-reduced intermediates upon exposure to air, as observed by CV. In contrast, dyes that have negative Hammett sigma values on one or both rings are I-substrates, and their one electron-reduced intermediates are relatively stable in air. In this study, we have investigated the susceptibility to microsomal azoreduction of monosubstituted dyes, with ring substituents possessing a wide range of Hammett sigma values. We have observed a direct correlation between the susceptibility of these compounds to microsomal azoreduction and the Hammett sigma constant of the aromatic ring substituent, and the presence of a positive potential in the dyes observed by CV. A Hammett sigma value of -0.37 or lower is required for substrate activity. Dyes with two substituents in the prime ring confirmed the previous correlation of negative and positive Hammett sigma values with I- and S-substrate activities, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: S
authors.initials: S
authors.lastname: Zbaida
authors.forename: C F
authors.initials: CF
authors.lastname: Brewer
authors.forename: W G
authors.initials: WG
authors.lastname: Levine
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000378:metabolism*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004583:Electrons; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D009601:Nitroreductases; D010084:Oxidation-Reduction; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D001391:Azo Compounds; D003577:Cytochrome P-450 Enzyme System; D009247:NADH, NADPH Oxidoreductases; D009601:Nitroreductases; C021106:azoreductase; C009850:azobenzene