Induction of Heme Oxygenase: A General Response to Oxidant Stress in Cultured Mammalian Cells1

Accumulation of heme oxygenase niRVV is strongly stimulated by treatment of cultured human skin fibroblasts with ultraviolet radiation, hydrogen peroxide, or the sulfhydryl reagent sodium arsenite (S. M. Keyse and R. M. Tyrrell. Proc. Nati. Acad. Sci. USA, «5:99-103, 1989). Since this will result in a transient reduction in the prooxidant state of cells, the phenomenon may represent an important inducible antioxidant defense mechanism. To examine the generality of the response, we have measured the accumulation of the specific niKN Vin a variety of human and mammalian cell types after inducing treatments. Induction by sodium arsenite is observed in all additional human cell types tested. This includes primary epidermal keratinocytes and lung and colon fibroblasts as well as established cell lines such as lÃ-ela, TK6 lymphoblastoid, and transformed fetal keratinocytes. Strong induction of heme oxygenase niK.YY is also observed following sodium arsenite treatment of cell lines of rat, hamster, mouse, monkey, and marsupial origin. The agents which lead to induction in cultured human skin fibroblasts fall into two cate gories: (a) those which are oxidants or can generate active intermediates (ultraviolet A radiation, hydrogen peroxide, menadione, and the tumor promoter, 12-0-tetradecanoylphorbol-13-acetate); (/>)agents which are known to interact with or modify cellular glutathione levels (buthionine sulfoximine, sodium arsenite, iodoacetamide, diamide, and cadmium chlo ride). These observations strongly support the hypothesis that induction of the enzyme is a general response to oxidant stress in mammalian cells and are consistent with the possibility that the cellular redox state plays a key role.