Induction of the expression of the mammalian heme oxygenase gene appears to be a general response to oxidant stress. In view of the role of glutathione in protecting cells against solar UVA radiation and other forms of oxidant stress, we have investigated the relationship between intracellular glutathione levels and the inducibility of the human heme oxygenase gene after treatment of populations of cultured skin fibroblasts with either UVA radiation or hydrogen peroxide. We observe a clear relationship between cellular glutathione status and both the constitutive and oxidant-inducible accumulation of heme oxygenase mRNA. Glutathione depletion may lead to enhanced gene expression either as a result of the potentiated accumulation of active oxygen intermediates or as a result of the direct influence of glutathione on a critical target involved in signal transduction.