Serial Review J. Clin. Biochem. Nutr., 42, 197–203, May 2008 HjtJ01SKchCo098ebyeur.18Bno3irS20a2tnN1-ol0a605,cRl040iJo8/e08ajvtf0c96pyi2bCae9fnwloi.2nr0iFc0ra8ele0B2Ri9oacdhiceaml iRstCersyeaarnrcdbhNoJunaptraMitnioonnoxide: Medicine Chemistry and Biological Effects eme Oxygenase and Guest Editor: Yuji Naito Integrative Survival Response Evoked by Heme Oxygenase-1 and Heme Metabolites Hyun-Ock Pae1,2,†, Eun-Cheol Kim3,†, and Hun-Taeg Chung1,4,* 1Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan 570-749, Republic of Korea 2Professional Graduate School of Oriental Medicine, Wonkwang University, Iksan 570-749, Republic of Korea 3Department of Oral and Maxillofacial Pathology, College of Dentistry, Wonkwang University, Iksan 570-749, Republic of Korea 4Genome Research Center for Immune Disorders, School of Medicine, Wonkwang University, Iksan 570-749, Republic of Korea ;52143R209aec073cc8eeivpetedd42.1.210.200808 Received 4 January, 2008; Accepted 21 January, 2008 CopySriugmhtm©a2r0y08 HJCeBmNe oxygenase (HO) catalyzes the rate-limiting step in heme degradation to produce carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently converted to bilirubin by its reductase, and iron is recycled for heme synthesis. The inducible HO isoform, HO-1, is involved in the protection of multiple tissues and organs. The mechanism of protec- tive actions of HO-1 has not been completely elucidated, but recent evidence suggests that one or more of heme metabolites can mediate the protective effects of HO-1. Particularly, CO mimics the antioxidant, anti-inflammatory, anti-apoptotic and antiproliferative actions of HO- 1. Many of these effects of CO depend on the production of cyclic guanosine monophosphate (cGMP), and the modulation of mitogen-activated protein kinase (MAPK) pathways. The transcription factors, including nuclear factor E2-related factor-2 (Nrf2), and their upstream kinases, including MAPK pathway, play an important regulatory role in HO-1 expression by dietary antioxidants and drugs. This review attempts to concisely summarize the molecular and biochemical characteristics of HO-1, with a discussion on the mechanisms of signal trans- duction and gene regulation that mediate the induction of HO-1 by dietary antioxidants and drugs. In addition, the cytoprotective roles of HO-1 shall be discussed from the perspective of each of the metabolic by-products. Key Words: heme oxygenase, antioxidant, anti-inflammation, anti-apoptosis, antiproliferation *To whom correspondence should be addressed. Tel: +82-63-850-6762 Fax: +82-63-851-5066 E-mail: htchung@wku.ac.kr †These authors contributed equally to this work. 197 Introduction Heme, a complex of ferrous iron and protoporphyrin IX, has a variety of biological functions, including oxygen binding, electron transport, and chemical catalysis [1]. Various types of proteins contain this molecule as their