GOLD

Source

As an occupational exposure, humans can come into contact with gold through metal mining and smelting. Gold is also prevalent in industrial uses because of it electrical and thermal conductivity. Medically, gold is used in the form of organogold salts (gold-carbon bonds) for the treatment of rheumatoid arthritis, gold complexes for their anti-tumor properties, and colloidal gold or gold nano-particles are used in electron microscopy [1].

Biotransformatiom

A recent study has been conducted with gold nanoparticles ranging from 4 to 22 nm. Researchers tracked the nanoparticles and discovered a 2-step biotransformation process. First was degradation of the smallest size particles first, mediated by NADPH oxidase in the lysosomes of the cell. Then recrystallization occurs with the gold forming 2.5 nm nanoleaves, this is strongly suspected to be due to metallothioeins [2].

Toxicokinetics

According to one article, 95% of gold is excreted through the feces when administered orally, and 70% is excreted through the urine when given parenterally. Peek concentration is reached in 2 to 6 hours after IM injection. The highest concentration of gold once circulating systemically is found in macrophages, liver, kidney, spleen and joints [3]. After continued therapy in rheumatoid arthritis patients, the concentration of gold in synovium is 10x that of muscle, bone, or fat [1].

Carcinogenicity

For occupational and industrial exposure to gold through mining, there has been an increase in incidence of pulmonary tumors [1].

Mechanism of Action (MoA)

The MoA is not fully understood, but as highlighted above, gold is rapidly phagocytosed into macrophages and inhibits their function. While this is the goal of anti-inflammatory medications, this can also cause adverse effects systemically.

Target Organs and Symptoms of Toxicity

Genetic Susceptibility

Studies have suggested a genetic predisposition to gold induced thrombocytopenia or proteinuria for those who have rheumatoid arthritis. Their findings were those that have the haplotype bearing B8,DR3, which carries DQA2 and DQB2 genes, are more likely be diagnosed with thrombocytopenia or proteinuria [4].

Treatments

Gold toxicity is treated by stopping the gold therapy and treating symptoms that have occurred. If treatment resumes and patients develop adverse effects again, alternative medication is required [5].

Biomarkers

One group of researchers recognized the novel ways gold nanoparticles are being used and decided to investigate potential biomarkers for gold toxicity. There study was conducted using 20 nm gold nanoparticles injected into rats. Their findings were  that gold nanoparticles caused an increase in 8-hydroxydeoxyguanosine (8OHdG), caspase-3 and heat shock protein70 (Hsp70), and IFN-γ, which all would lead to inflammation and cell damage. They also saw a decrease in seratonin and dopamine levels in the treated animals, indicating there could be neurotransmitters affected as well [6].

References:

1. Tokar E, Boyd W, Freedman J, Waalkes M. Casarett and Doull’s Toxicology: The Basic Science of Poisons, 8th Edition. Chapter 23: Toxic Effects of Metals.
2. Balfourier A, Luciani N, Wang G, Lelong G, et al. Unexpected intracellular biodegradation and recrystallization of gold nanoparticles. PNAS. 2020 January 7. 117 (1) 103-113. https://doi.org/10.1073/pnas.1911734116
3. Juan H. The Pharmacology of Gold Compounds. Wien Klin Wochenschr Suppl. 1984;156:7-13. Available from: https://pubmed.ncbi.nlm.nih.gov/6442062/
4. Singal D, Reid B, Green D, D’Souza M, Bensen W, Buchanan W. Polymorphism of major histocompatibility complex extended haplotypes bearing HLA-DR3 in patients with rheumatoid arthritis with gold induced thrombocytopenia or proteinuria. Annals of the Rheumatic Diseases. 1990 Aug; 49(8): 582–586. doi: 10.1136/ard.49.8.582
5. Gold Toxicity. DoveMed. 2018 May 28. Available from:  https://www.dovemed.com/diseases-conditions/gold-toxicity/
6. Siddiqi N, Abdelhalim M, El-Ansary A, Alhomida A, Ong W. Identification of Potential Biomarkers of Gold Nanoparticle Toxicity in Rat Brains. Journal of Inflammation. 2012 Jun 12;9:123. doi: 10.1186/1742-2094-9-123.