198 H.-O. Pae et al. prosthetic group. When these proteins turn over, the heme is not salvaged but degraded by the enzyme heme oxygenase (HO) [2]. HO catalyzes the first and rate-limiting step in the oxidative degradation of free heme to produce equimolar quantities of carbon monoxide (CO), ferrous iron, and biliverdin (BV) [3]. BV is subsequently converted to bilirubin (BR) by a BV reductase, and iron is recycled for heme synthesis. Two genetically distinct isozymes of HO have been characterized: an inducible form, heme oxygenase- 1 (HO-1), and a constitutively expressed form, heme oxygenase-2 (HO-2). Although both HO-1 and HO-2 catalyze the identical biochemical reaction, they differ in genetic origin, in primary structure, in molecular weight, and in their substrate and kinetic parameters [4]. Moreover, HO-1, once expressed, can metabolize high amounts of free heme to produce high concentrations of its enzymatic by- products that may affect various biological events. HO-1 can be expressed primarily by its substrate, free heme, and also by a wide variety of stimuli, inducing hypoxia, hyperoxia, pro-inflammatory cytokines, nitric oxide (NO), heavy metals, ultraviolet radiation, heat shock, shear stress, and hydrogen peroxide [4, 5]. This adaptive response of HO-1 to these cytotoxic stimuli implies that HO-1, besides its role in heme degradation, may function as a critical cytoprotective molecule. This review attempts to concisely summarize the mole- cular and biochemical characteristics of HO-1, with a dis- cussion on the important mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 particularly by dietary antioxidants and drugs. In addition, the integrative survival response evoked by HO-1 shall be discussed from the perspective of each of the metabolic by- products. HO-1 Deficiency Essential lessons from the analysis of HO-1-deficient human case and mice indicate that HO-1 is involved in the protection of multiple tissues and organs and that cyto- protection afforded by HO-1 is associated with its anti- oxidant, anti-inflammatory, anti-apoptotic and antiprolifera- tive effects. Mice Poss and Tonegawa [6, 7] have first reported that HO-1- deficient mice are extremely sensitive to oxidative injury, thus establishing that HO-1 is an important cytoprotective system. The HO-1-deficient mice exhibited a decreased birth rate, growth retardation, anemia, tissue iron deposition, hepatosplenomegaly, lymphadenopathy, leukocytosis, and glomerulonephritis [8]. The HO-1-deficient mice developed a chronic inflammatory state that progresses with age [9]. Human Yachie and colleagues [10–12] have reported the first human case of HO-1 deficiency in a 6-yr-old boy. The child suffered from similar symptoms as the HO-1-deficient mice, including growth failure, anemia, increased iron binding capacity, tissue iron deposition, lymphadenopathy, leuko- cytosis, and increased sensitivity to oxidant injury [8]. The HO-1-deficient human case died of an inflammatory syndrome [8, 11]. HO-1 Expression A number of intracellular signaling molecules and their downstream transcription factors have been identified to involve HO-1 expression [13]. Among them, the mitogen- activated protein kinase (MAPK), as one of upstream pathways, and the nuclear factor E2-related factor 2 (Nrf2), as one of downstream transcription factors, are well described to be more important in HO-1 expression by non- toxic phytochemicals and drugs [13, 14], and thus briefly discussed below (Fig. 1). MAPK pathway The MAPK super-family comprises three primary signaling cascades: the extracellular signal regulated kinase (ERK), the c-Jun NH2-terminal kinase or stress-activated kinase (JNK/SAPK), and the p38 MAPK. Recent studies have focused on the roles of MAPK pathways in HO-1 expression in diverse cell types in response to various stimuli [14]. For examples, curcumin stimulates HO-1 expression through p38 MAPK pathway [15–18]. α-Lipoic acid induces HO-1 expression through ERK pathway [19]. Paclitaxel induces the expression of HO-1 via JNK pathway [20]. Interestingly, the inhibition of ERK, JNK, or p38 MAPK activation individually is insufficient to completely abolish HO-1 expression by oxidized low density lipo- protein; however, inhibition of these MAPK pathways in combination results in a significantly greater attenuation of HO-1 expression [21], suggesting that these MAPK path- ways act in concert to regulate HO-1 expression. Nrf2 activation Nrf2 is a member of the basic leucine zipper family of transcription factors. Under normal physiological condi- tions, Nrf2 resides in the cytoplasm bound to its inhibitor protein, Keap-1, an actin-binding protein. On stimulation, Nrf2 is released from Keap-1 and rapidly translocates into the nucleus, where it binds to a DNA sequence in target genes [22]. The important role of Nrf2 in the stress- dependent expression of HO-1 has been highlighted by the finding that HO-1 is less inducible in Nrf2-deficient mice [23]. Moreover, transduction of vascular smooth muscle cells with Nrf2-expressing adenovirus increased cyto- J. Clin. Biochem. Nutr.