Cellular iron depletion weakens induction of heme oxygenase-1 by cadmium

Abstract

Heme oxygenase-1 is an inducible cytoprotective gene, although its induction by environmental factors is not completely understood. This study aimed to ascertain if specific nutritive factors or related compounds influence heme oxygenase-1 expression. In HCT-116 cells, cadmium increased heme oxygenase-1 enzymatic activity. This effect of cadmium was weaker in cells made iron-deficient with the iron chelator, desferrioxamine, which was associated with repression of heme oxygenase-1 protein and mRNA expression. The repression by desferrioxamine of cadmium-induced heme oxygenase-1 upregulation was reversed upon iron replenishment of the cells. Additionally, it was found that thiol antioxidants inhibited the heme oxygenase-1 upregulation caused by cadmium and also by ethacrynic acid, which each decreased intracellular glutathione as did buthionine sulfoxamine. Interestingly, cadmium and ethacrynic acid increased nuclear translocation of Nrf2 and subsequent heme oxygenase-1 expression, but buthionine sulfoxamine did not. Furthermore, NADPH oxidase inhibitors (diphenyleneiodonium and apocynin, and a superoxide scavenger (Tiron) inhibited cadmium-induced upregulation of heme oxygenase-1. Diphenyleneiodonium was the most potent and inhibited NADPH-cytochrome P450 reductase as well, whereas apocynin and Tiron did not. It is concluded that adequate amounts of iron, which at the atomic level can serve as the pivotal element of heme in NADPH oxidase, must be present in cells to permit what appears to be thiol redox-sensitive, NADPH oxidase-dependent upregulation of heme oxygenase-1. Thus, these findings are significant because they suggest that cells without adequate iron would be unable to fully express the stress gene, heme oxygenase-1, when confronted with the toxic metal, cadmium.

Liver and Cadmium Toxicity

“…Cd has been shown to bind to both ferritin and apoferritin, and to displace Fe from various intracellular sites [58]. Recently, Lai and Loo [60], reported that cells without adequate Fe would be unable to fully express the stress gene, heme oxygenase-1, when confronted with the toxic metal, Cd (Figure 2). …”

Untitled

“…HMOX1 is mapped at chromosome 22q13.1. An induction of HMOX1 by multifaceted stressors, like cadmium 29 , inflammatory stimuli 30 , and oxidative stressors 31 is well documented and may protect cells under various stress conditions in the endothelium. The HMOX1 gene product is a membrane-bound enzyme (GO: 0043231), localized to microsomes (GO: 0005792) and the endoplasmic reticulum (GO: 0005783).…”

Flipside of the Coin: Iron Deficiency and Colorectal Cancer

“…As well as being involved in cellular homeostasis, HO-1 plays an important part in preventing oxidative tissue damage and mediating intracellular inflammatory mechanisms, apoptosis and cell proliferation (85). Lai et al (87) reported that without adequate iron, HCT-116 human colon adenocarcinoma cells were unable to express the HO-1 gene completely, in response to toxicity. Since iron is essential for HO-1 gene expression, iron deficiency might lead to decreased cytoprotection through HO-1 expression (20).…”