Deck 27: Ndustrial Chemicals That Change Lipophilicity but Do Not Biodegrade: Metal Impacts

Question 1

How is As toxicity manifested?

Answer 1

The skin toxicity, cancer, diabetes mellitus, cardiovascular toxicity, neurotoxicity, and nephrotoxicity are started when the first methylation reaction is used to try to remove it from the body. The ϖ isoform of GSH S-transferase and purine nucleoside phosphorylase catalyze the reduction of As(V) to the more toxic As(III). Polynucleotide phosphorylase and mitochondrial ATP synthase also do this reduction in the presence of GSH. As non-conjugated arsenicals are highly reactive with thiols and easily converted to less toxic pentavalent arsenicals, the As(III)-GSH conjugate may be a key factor in As toxicity.

Question 2

Why does Cd focus on the kidney for its toxic action?

Answer 2

Cd is especially known for renal proximal tubule damage to S1 and S2 segments
(apoptosis). This is caused by endoplasmic reticulum (ER) stress. ER stress transducers
(RNA-dependent protein kinase-like ER kinase [PERK]), activating transcription factor 6 (ATF6), and inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) are generated. ATF6 activates apoptosis through induction of CCAAT/enhancer-binding protein-homologous protein (CHOP), while IRE1 produces apoptosis by stimulation of X-box binding protein 1 (XBP1) and subsequent phosphorylation of c-jun N-terminal kinase (JNK). ER stress also leads to Ca2 release and induction of apoptosis (calpain-caspase signal transduction pathway). Cd also acts directly on kidney mitochondria causing mitochondrial swelling and cyt c release. Cd also affects Ub-proteasome system responsible for degradation of damaged proteins. At high concentrations, Cd causes a painful deterioration of bones (Itai-Itai disease). Chronic exposure can lead to liver or kidney tumors and diabetes mellitus.

Question 3

Why is cobalt a nutrient and a toxicant?

Answer 3

Cobalt is only a nutrient as part of vitamin B₁₂, but as a metal (inorganic form) had been used clinically to stimulate erythropoietin production by the kidney to treat anemias and protect against hypoxia via inducing HIF, heme oxygenase, and metallothionein (also prevents oxidative damage following hypoxia). Co excess cause goiter via inhibition of tyrosine iodonase, co-asthma and hard metal disease (lung damage), allergic contact dermatitis (skin exposure), immune alterations, and possibly cancer. Co in beer in the 1960s caused cardiomyopathy. Like other heavy metals, Co has affinity for -SH
groups and thereby inhibits mitochondrial respiration. Co also generates ROS via Fenton-like reactions. Induction of HIF most likely associated with cancer. At high concentrations, Co ions and nanoparticles lead to cytotoxicity with cells experiencing apoptosis or necrosis depending on signaling and the degree of damage.

Question 4

Lithium is used to treat bipolar disease. What are its adverse effects?