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 defe nse mechanism. The objectives of this study were to characterize the i nduction of heme oxygenase by the oxidant stress-inducing quinone agen t menadione (2-methyl-1,4-napthoquinone) and to elucidate the roles of basal and induced heme oxygenase enzyme activities in menadione-induc ed DNA damage and growth inhibition in human MCF-7 cells. Time- and do se-dependent inductions of heme oxygenase messenger RNA and enzyme act ivity in menadione-treated MCF-7 cells were demonstrated. Intracellula r and extracellular bilirubin concentrations were less than 100 nmol/L and were not altered when heme oxygenase was induced. The roles of th e basal and induced heme oxygenase enzyme activities in menadione-medi ated DNA damage were evaluated by means of the heme oxygenase competit ive inhibitor tin protoporphyrin. Inhibition of the basal heme oxygena se enzyme activity by tin protoporphyrin resulted in a decrease in the number of menadione-induced DNA breaks and an attenuation of the cell ular 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 li nes were significantly less than that measured in a menadione-sensitiv e 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 effect s engendered by menadione in human cells.