Heme oxygenase does not protect human cells against oxidant stress.
The induction of heme oxygenase in cells under conditions of oxidative stress has been hypothesized to represent a cellular antioxidant defense mechanism. The objectives of this study were to characterize the induction of heme oxygenase by the oxidant stress-inducing quinone agent menadione (2-methyl-1,4-naphthoquinone) and to elucidate the roles of basal and induced heme oxygenase enzyme activities in menadione-induced DNA damage and growth inhibition in human MCF-7 cells. Time- and dose-dependent inductions of heme oxygenase messenger RNA and enzyme activity in menadione-treated MCF-7 cells were demonstrated. Intracellular and extracellular bilirubin concentrations were less than 100 nmol/L and were not altered when heme oxygenase was induced. The roles of the basal and induced heme oxygenase enzyme activities in menadione-mediated DNA damage were evaluated by means of the heme oxygenase competitive inhibitor tin protoporphyrin. Inhibition of the basal heme oxygenase enzyme activity by tin protoporphyrin resulted in a decrease in the number of menadione-induced DNA breaks and an attenuation of the cellular growth inhibition caused by menadione. Induced heme oxygenase did not protect MCF-7 cells from menadione-induced DNA breaks. Basal heme oxygenase enzyme activities in two cloned menadione-resistant cell lines were significantly less than that measured in a menadione-sensitive parental MCF-7 cell line. Collectively, these data do not support a protective role for basal or induced heme oxygenase enzyme activities against oxidant stress-related DNA strand breakage or cytotoxic effects engendered by menadione in human cells.
Nutter
L M
LM
Department of Pharmacology, Medical School, University of Minnesota, Minneapolis 55455.
Sierra
E E
EE
Ngo
E O
EO
D001663:Bilirubin / Q000096:biosynthesis; D004249:DNA Damage; D004790:Enzyme Induction / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology*
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014812:Vitamin K; D006419:Heme Oxygenase (Decyclizing); D001663:Bilirubin