Interaction of epinephrine metabolites with the liver microsomal electron transport system
Uemura, T.; Chiesara, E.; Cova, D.
Molecular Pharmacology 13(2): 196-215
1977
ISSN/ISBN: 0026-895X PMID: 16206 Document Number: 114588
3,4-Benzpyrene hydroxylase activity, NADPH-neotetrazolium reductase activity, and the NADPH-dependent lipid peroxidation reaction were inhibited by 100 .mu.M epinephrine about 70, 50 and 70%, respectively, using either NADPH or an NADPH-generating system consisting of NADPH and glucose 6-phosphate dehydrogenase. [Rat liver microsomes were used.] On the other hand, inhibition of benzpyrene hydroxylase and NADPH-neotetrazolium reductase activity by epinephrine was abolished using NADP and the soluble fraction as NADPH-generating system. Epinephrine itself did not have an inhibitory effect on these 2 enzymes activities; inhibition was due partly to electron transfer to epinephrine through superoxide-anion radical .**GRAPHIC**. at the level of NADPH-cytochrome c reductase and partly to the adrenochrome produced by epinephrine oxidation. It was proved that adrenochrome itself was metabolized by liver microsomes consuming NADPH and transformed into leukoadrenochrome, probably via adrenochrome semiquinone, which may also have an inhibitory effect on benzpyrene hydroxylase even though it was much less effective than adrenochrome. The soluble fraction contained a heat-stable protein factor that blocked adrenochrome formation, reducing the inhibition of benzpyrene hydroxylase and NADPH-neotetrazolium reductase activities by epinephrine. This heat-stable protein factor was purified by a fairly simple method and identified as superoxide dismutase (hepatocuprein) from its spectrophotometric and EPR spectra and its capacity to scavenge .**GRAPHIC**. The purified hepatocuprein alone, like the crude heated soluble fraction, had no inhibitory effect on the microsomal hydroxylation reaction and could not prevent the inhibitory action of adrenochrome. Like the heated soluble fraction, it only reduced the inhibitory action of epinephrine on microsomal benzpyrene hydroxylase activity. The addition of purified hepatocuprein alone significantly inhibited the microsomal NADPH-dependent lipid peroxidation reaction at high ionic strength. It could not block the inhibitory effect of epinephrine on the lipid peroxidation reaction as did the crude soluble fraction. Another mechanism may be operative for the lipid peroxidation reaction, because inhibition was not affected by either the soluble fraction or the purified hepatocuprein. The inhibitory mechanism of epinephrine metabolites toward the microsomal mixed-function oxidase system and the mode of action of hepatocuprein are discussed.