Distinct protective mechanisms of HO-1 and HO-2 against hydroperoxide-induced cytotoxicity

Yun Sook Kim, Hean Zhuang, Raymond C. Koehler, Sylvain Doré

Research output: Contribution to journalArticlepeer-review

54 Scopus citations


Heme oxygenases (HO-1 and HO-2) catalyze the NADPH-cytochrome P 450 reductase (CPR)-dependent degradation of heme into iron, carbon monoxide, and biliverdin, which is reduced into bilirubin. Under basal conditions, HO-1 is often undetected and can be induced by numerous stress conditions. Although HO-2 is constitutively expressed, its activity appears to be regulated by post-translational modifications. HO activity has been associated with cellular protection, by which it degrades heme, a prooxidant, into bioactive metabolites. Under given circumstances, overexpression of HO-1 can render cells more sensitive to free radicals. Here, we investigated the properties of human HO isoforms that protect against oxidative stress. Considering that CPR can be a limiting factor for optimal HO activity, we tested stable HO-1 and HO-2 cell lines that derived from the CPR cells. Results indicate that the HO-1 and HO-2 cells are more resistant than controls to hemin and to the organic tert-butyl hydroperoxide, t-BuOOH. However, HO-1 cells are less resistant than HO-2 cells to hydrogen peroxide (H 2O 2). The levels of oxidatively modified proteins of HO-1 and HO-2 cells in response to t-BuOOH toxicity are identical, but the level of oxidatively modified proteins of HO-2 cells is less than that of HO-1 cells in response to H 2O 2 toxicity. Performing subcellular fractionations revealed that HO-2 and CPR are found together in the microsomal fractions, whereas HO-1 is partially present in the microsome and also found in other fractions, such as the cytosol. These same findings were observed in non-transfected primary neurons where HO-1 proteins were chemically induced with 15-deoxy-Δ 12,14-prostaglandin J 2 (15dPGJ 2). The differences in subcellular localization of HO-1 and HO-2 could explain some of the discrepancies in their cellular activity and enzymatic protective mechanisms.

Original languageEnglish (US)
Pages (from-to)85-92
Number of pages8
JournalFree Radical Biology and Medicine
Issue number1
StatePublished - Jan 1 2005


  • Cytochrome P reductase
  • Endoplasmic reticulum
  • Free radicals
  • Heme oxygenase
  • Microsome
  • Prostaglandins
  • Subcellular localization

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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