Decrease in NADPH-cytochrome P450 reductase activity of the human heart, Liver and lungs in the presence of alpha-lipoic acid.
BACKGROUND
NADPH-cytochrome P450 reductase (CPR) is the electron donor protein for several oxygenase enzymes located in the endoplasmic reticulum. These oxygenases include P450 family enzymes involved in the metabolism of endogenous and exogenous substances. The enzyme is involved in adriamycin (anticancer drug) and paraquat (herbicide) toxicity. CPR is a flavoprotein containing both flavine-adenine dinucleotide and flavine mononucleotide. A structural study showed the presence of several sulfhydryl (SH) groups in the CPR molecule. Some of them play a key role in catalytic activity. As alpha-lipoic acid contains a disulfide bond, it may react with the SH group of CPR. The aim of the study was to evaluate the effect of alpha-lipoic acid on human P450 reductase activity.


METHODS
The activity of the enzyme was determined by measuring the rate of cytochrome c reduction at 550 nm, in vitro, using heart, liver and lung microsomes.


RESULTS
The activity of CPR was decreased in all organs after addition of alpha-lipoic acid to the reaction mixture at concentrations of 0.01, 0.10 and 1.00 mM. The decreases in CPR activity were concentration-dependent and the sequence of relative inhibition was as follows: heart >lung >liver. However, the statistical significance of CPR activity vs. control was observed in the heart in the presence of 1.00 mM alpha-lipoic acid and in the lung at 0.10 and 1.00 mM alpha-lipoic acid.


CONCLUSIONS
alpha-Lipoic acid decreased NADPH-CPR activity in the lung and heart. The present results are promising for future studies to obtain the most effective antidote for adriamycin and paraquat toxicity.
Dudka
Jaroslaw
J
Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland. ave123@wp.pl
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism*; D009928:Organ Specificity; D010269:Paraquat / Q000037:antagonists & inhibitors / Q000633:toxicity; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D008063:Thioctic Acid; D004317:Doxorubicin; D009251:NADPH-Ferrihemoprotein Reductase; D010269:Paraquat