Multiple mechanisms in hepatic microsomal azoreduction.
1. Microsomal reduction of azo dyes related to dimethylaminoazobenzene (DAB) is catalysed by at least two types of cytochrome P-450. The first is selectively induced by clofibrate. The second is induced by phenobarbital, beta-naphthoflavone, isosafrole, and pregnenolone-16 alpha-carbonitrile, as well as clofibrate. 2. Azoreduction by the first type of P-450 is insensitive to both O2 and CO and involves dyes with only electron-donating substituents (I substrates). 3. Azoreduction by the second type of P-450 is inhibited by both O2 and CO and involves dyes with electron-withdrawing as well as donating substituents (S substrates). 4. All azo dye substrates exhibit two negative and one positive redox potential, as measured anaerobically by cyclic voltammetry. The negative potentials reflect one- and two-electron reductions while the positive potential permits electron transfer from microsomal P-450, the redox potential for which is reported to be negative (approximately 0.35 V). The positive potential is associated with a polar electron-donating group para to the azo linkage, which is an absolute requirement for microsomal reduction. Dyes without this functional group do not exhibit positive potentials and are not reduced. 5. The first negative potential of S substrates is quenched upon admitting air to the system, whereas this potential is unaffected in I substrates. The relative stability of the one-electron reduced state may be an explanation for the differential O2 sensitivity of I and S substrate reduction.
Levine
W G
WG
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461.
Stoddart
A
A
Zbaida
S
S
D000818:Animals; D001391:Azo Compounds / Q000378:metabolism*; D004396:Coloring Agents / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D004124:p-Dimethylaminoazobenzene / Q000378:metabolism
D001391:Azo Compounds; D004396:Coloring Agents; D003577:Cytochrome P-450 Enzyme System; D004124:p-Dimethylaminoazobenzene; D010100:Oxygen