Owing to its high toxicity and cumulative potential, minimizing the Cd contamination of the food chains and reducing Cd levels in food crops to the lowest achievable levels are essentially preventive public measures. Here, we discuss the frontline cellular stress response that may be a complementary measure to mitigate harmful effects of inevitable exposure to such a toxicant as Cd.

HO-1 and HO-2 are enzymes involved in the degradation of heme to retrieve Fe for reuse by cells and to generate cytoprotective molecules, carbon monoxide (CO) and biliverdin IXα from which bilirubin is rapidly generated [109,110,111]. The economy of Fe utilization requires the salvaging of Fe, so the bulk of Fe released by the action of HO-1 and HO-2 is reutilized in the synthesis of hemoproteins, such as nitric oxide synthase, various enzymes of the mitochondrial respiratory chain, and the cytochrome P450 super family [112]. In every nucleated cell of the body, heme degradation and de novo biosynthesis of heme are indispensable and simultaneous induction of MT and HO-1 occurs in most nucleated cells of the body in response to Cd exposure [32,109,110,113].

Serum bilirubin, a product of normal heme degradation and the catalytic activity of biliverdin XI-α reductase, contributes mostly to the total antioxidant capacity of blood plasma [114,115,116]. Due to its lipophilic properties, bilirubin is a lipid peroxidation chain breaker that protects lipids from oxidation more effectively than the water-soluble antioxidants, such as glutathione [115,116]. The ability of bilirubin to inhibit the oxidation of low-density lipoprotein accounts for the association observed between higher total serum bilirubin levels and lower risks of metabolic syndrome and non-alcoholic liver disease [117]. Of note, recent experimental data show that Cd-activated HO-1 gene and heme degradation did not result in formation of bilirubin [118]. A further discussion is in Section 5.

Synthetic carbon monoxide-releasing molecules (CORM) were used to study effects of CO on mitochondrial biogenesis [119,120,121]. In high doses, CO has anti-inflammatory, anti-apoptotic, and vasodilatory effects and is cardioprotective. In low levels achievable through induction of HO-1 expression, CO increases the generation of reactive oxygen species (ROS) by the mitochondria, presumably through the inactivation of cytochrome C oxidase (COX) [119]. The elevated ROS then activates the PI3K/AKT signaling pathway, causing the inhibition of glycogen synthase kinase 3 β (GSK3β) and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) [122]. CO, p62, and NAD(P)H dehydrogenase quinone 1 (NQO1) are all required for the biogenesis of mitochondria and the removal of mitochondria with severe damage [122,123]. Mitochondrial ROS production is a mechanism that cells use to increase their capacity to adapt to stress [124,125]. Thus, HO-1 induction represents an important cellular stress response mechanism. The repression of this stress response gene is equally important to sustain the cellular redox state.

HO-1 and HO-2 are products of two different genes [126]. The promoter of the human HO-1 gene is unique because it contains the GT repeats, not found in rodent or murine species [109,110,111]. The genetic polymorphisms, such as long GT repeats, are associated with an elevated risk for various diseases, type 2 diabetes included [127,128].

Cellular expression of HO-1 is regulated by the transcription factor, including CLOCK, Bmal, and Per, that work together to generate day–night cyclical expression of the genes involved in energy metabolism [129,130,131,132]. Disruption of the diurnal cycle caused obesity in mice [133]. Expression of the HO-1 gene is controlled also by heme (its own substrate), the levels of glucose, oxygen, and shear stress [109,110,134,135].

The catalytic domains of HO-1 and HO-2 are highly homologous, sharing 93% of their amino acid sequences. HO-2, however, contains an additional domain, which has Cys-Pro dipeptide motifs that allows binding of heme and interacting with other proteins that include Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways [136,137,138].

In addition to heme degradation activity, HO-2 has a regulatory role that was unraveled from obese and diabetic mice lacking HO-2 expression. HO-2 deficiency in mice caused neither lethality nor infertility, and HO-2 deficient mice underwent normal development to adulthood when they display the symptomatic spectrum of human type-2 diabetes, hyperglycemia, increased fat deposition, insulin resistance, and hypertension with aging [139,140,141]. The normal development and normal fecundity in the absence of HO-2 expression suggested that HO-1 could compensate for the heme-degradation activity of HO-2. However, HO-1 did not compensate for the anti-diabetogenicity and anti-obesity of HO-2.

In a protein microarray study, HO-2 was linked to the glycolytic pathway through its interaction with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) [142]. In liver, PFKFB4 is the key regulator of glycolysis [143], and a lack of HO-2 expression causes persistent hyperglycemia due to an impaired ability to suppress glucose production. Cd may mimic this effect of HO-2 deficiency, thereby causing hyperglycemia. Both HO-1 and HO-2 are required to prevent a fall of blood glucose during fasting or a rise in blood glucose in a post-absorptive period. HO-2 expression ensures PFKFB4 expression.

In the liver of wild-type mice, lowered glycolysis with enhanced gluconeogenesis could be achieved in fasting state by HO-1 up-regulation plus PFKFB4 down-regulation. In the post-absorptive state, high glycolysis with suppressed gluconeogenesis could be achieved by HO-1 down-regulation plus HO-2 and PFKFB4 up-regulation. HO-1 protein expression levels in the liver of HO-2 knockout mice fell by 35–40% [144]. A possible consequence of a reduction in expression levels of HO-1 is increased susceptibility to oxidative damage. However, such repression of the HO-1 gene expression is an essential metabolic adaptation to safeguard the cellular redox state. This is achieved by utilizing NADPH (H⁺) for regenerating reduced glutathione (GSH) rather than for heme catabolism [142]. GSH recycling is a mechanism for maintaining cellular redox state. It is central to normal protein folding and cell function.

Several therapeutic drugs, such as statins (lipid lowering agents), rosiglitazone (anti-diabetic drug), aspirin (anti-inflammatory drug), paclitaxel and rapamycin (anti-cancer drugs), have been shown to induce HO-1 expression. The therapeutic efficacy of these drugs may be attributable, at least in part, to HO-1 induction [116,117].

A wide range of antioxidants from plant foods, such as curcumin, quercetin, tert-butylhydroquinone, and caffeic acid phenethyl ester, are HO-1 inducers, as are catechin (in green tea), α-lipoic acid (in broccoli, spinach), resveratrol (in red wine, grapes), carnosol, sulforaphane (cruciferous vegetable), coffee diterpenes cafestol, and kahweol [138,139,140,146,147,148]. Beneficial effects of consumption of these antioxidants could thus be mediated in part through the induction of HO-1 expression.

Diet high in anti-oxidative and anti-inflammatory nutrients was associated with increased serum bilirubin levels and reduced oxidative stress and systemic inflammation [104]. Green tea consumed in usual amounts was found to increase HO-1 expression [149,150,151]. One of the trials included only non-smoking diabetic subjects who had no history of metabolic complications and did not take regular food supplements [150]. Among 43 subjects, 23 had the long GT repeats (GT repeats ≥ 25; L/L genotype) type of the HO-1 promoter and another 20 had short GT repeats (GT repeats < 25; S/S genotype). According to Western blotting and the comet assay, HO-1 protein levels in circulating lymphocytes were increased by 40%, while the level of the DNA repair enzyme 8-oxoguanine glycosylase (hOGG1) was increased 50% with DNA damage being reduced by 15%. Green tea consumption increased HO-1 protein levels in lymphocytes in both L/L and S/S genotype groups, although the S/S group showed higher HO-1 protein levels at baseline, compared to the L/L group. This trial showed that green tea consumption may reduce cellular DNA damage through induced expression of HO-1.