Membrane-mediated effects of catecholamines on the DNA of human leukocytes: the role of reactive oxygen species.
The effects of epinephrine and two other beta 2-adrenergic agonists, ritodrine and isoxsuprine, on the induction of damage to the DNA (production of strand breaks) in human leukocytes were studied by fluorescence analyses of unwinding DNA. Epinephrine stimulated the development of DNA strand breaks. Ritodrine and isoxsuprine inhibited this effect of epinephrine on the human leukocytes by competition for binding to receptors, but they were not oxidized to the same extent as epinephrine. Metoprolol, which acts predominantly as a beta 1-antagonist, demonstrated a beta 2-antagonism, as compared with epinephrine. Since the o-oxidation of epinephrine involves the production of damaging oxygen species such as O2-. and H2O2, we studied the effects on DNA of extracellular H2O2 in the presence and absence of epinephrine. Extracellular H2O2 induced significant damage to the DNA, but it had a smaller effect when applied with epinephrine. The results obtained with 3-amino-1,2,4-triazole, an inhibitor of endogenous catalase, were not significantly different from control results, under our experimental conditions. Nevertheless, this compound had a mitigating effect when applied with epinephrine. We also investigated the action of nicotinamide in the presence and absence of epinephrine. The results demonstrated the importance of nicotinamide in cellular oxidative stress. Two antioxidant enzymes, superoxide dismutase and catalase, inhibited the epinephrine-induced damage to DNA.
Crespo
M E
ME
Laboratory of Endocrinology, Portuguese Cancer Institute Francisco Gentil, Lisboa, Portugal.
Bicho
M P
MP
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004338:Drug Combinations; D004837:Epinephrine / Q000494:pharmacology*; D005470:Fluorometry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007556:Isoxsuprine / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D008566:Membranes / Q000502:physiology; D008790:Metoprolol / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012312:Ritodrine / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D000975:Antioxidants; D004338:Drug Combinations; D017382:Reactive Oxygen Species; D004247:DNA; D006861:Hydrogen Peroxide; D008790:Metoprolol; D012312:Ritodrine; D007556:Isoxsuprine; D004837:Epinephrine