The Capture of Cadmium by Reactive Polysulfides Attenuates Cadmium-Induced Adaptive Responses and Hepatotoxicity

Abstract

Cadmium (Cd) is an environmental electrophile that modifies protein nucleophiles, thereby modulating cellular signaling and toxicity. While reactive persulfides/polysulfides exhibit relatively high nucleophilic properties, their roles in the altered gene expression and toxicity caused by Cd remain unclear. Exposing primary mouse hepatocytes to Cd caused heat shock protein 70 (HSP70) and metallothionein (MT)-I/II to be upregulated and cytotoxicity to occur. These effects were blocked in the presence of polysulfide sodium tetrasulfide (NaS). Electrospray ionization mass spectrometry analysis indicated that cadmium sulfide (CdS) and cadmium thiosulfate (CdSO) were produced when Cd reacted with NaS. Authentic CdS did not cause cellular signaling responses to be activated or hepatotoxic effects, while CdSO had effects similar to those of Cd. HSP70 and MT-I/II upregulation and hepatotoxicity caused by exposure to Cd were significantly enhanced by the deletion of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive persulfides/polysulfides. Deleting CSE also exacerbated Cd-mediated liver injury, whereas little hepatic damage was found when CdS or NaS along with Cd was administered. Overall, the results suggest that the persulfide/polysulfide-mediated formation of sulfur adducts of Cd such as CdS rather than CdSO is, at least in part, involved in decreasing the level of Cd-mediated activation of cellular signaling and toxicity.

Nrf2 Activation and Its Coordination with the Protective Defense Systems in Response to Electrophilic Stress

“…This indicates that RSS are involved in the repression of electrophile-mediated toxicity by the formation of inactive metabolites of electrophiles. Consistent with this notion, the toxicity of MeHg, Cd and 1,4-NQ was effectively blocked by treatment with the model polysulfide Na 2 S 4 [75,77,80].…”

“…As noted above, electrophiles can be captured by RSS, leading to the formation of their sulfur adducts. For example, we previously reported that MeHg, Cd, 1,4-NQ and NAPQI, which is the toxic metabolite of acetaminophen, can react with RSS, such as H 2 S, CysSSH, GSSH, GSSSG or the model polysulfide Na 2 S 4 , leading to the formation of bismethylmercury sulfide [(MeHg) 2 S], cadmium sulfide (CdS), CdS 2 O 3 , 1,4-NQ-SH, 1,4-NQ-S-1,4-NQ, 1,4-NQ-S-1,4-NQ-OH, NAPQIH 2 -SSSCys, NAPQIH 2 -SSCys and NAPQIH 2 -SSG [5,12,[75][76][77][78]. Additionally, (MeHg) 2 S and NAPQIH 2 -SSSCys were identified as novel metabolites of MeHg and acetaminophen from the liver and urine of mice treated with these compounds [78,79].…”

“…Additionally, (MeHg) 2 S and NAPQIH 2 -SSSCys were identified as novel metabolites of MeHg and acetaminophen from the liver and urine of mice treated with these compounds [78,79]. Remarkably, sulfur adduct electrophiles such as (MeHg) 2 S, CdS and 1,4-NQ-S-1,4-NQ-OH are less electrophilic and toxic than their parent compounds; thus, they are defined as detoxified metabolites [75][76][77]. This indicates that RSS are involved in the repression of electrophile-mediated toxicity by the formation of inactive metabolites of electrophiles.…”

“…Furthermore, knockdown of CSE enhanced Cd-induced cytotoxicity, whereas overexpression of CSE protected cells from this electrophile-induced cytotoxicity [83]. In vivo studies have shown that CSE deletion in mice causes increased sensitivity to acetaminophen-induced hepatotoxicity, Cd-induced hepatotoxicity and MeHg-induced toxicity [20,77,84]. Overall, this suggests that CSE is a crucial factor engaged in the protection against electrophiles because this enzyme is involved in the production of RSS, thereby capturing electrophiles to yield their sulfur adducts [5,85] (Figure 3).…”

H2S, Polysulfides, and Enzymes: Physiological and Pathological Aspects

“…In bovine aortic endothelial cells, CSE knockdown potentiated Cd-induced cytotoxicity but CSE overexpression provided protection [43]. In vivo experiments showed that CSE-knockout mice were sensitive to Cd-induced hepatotoxicity [44]. Adaptive changes in the activity and expression of CGL, MST, and TST in various frog tissues in response to exposure to lead, mercury, and cadmium confirmed the protective function of these enzymatic proteins against electrophilic stress [45,46].…”