Arsenic Toxicity: Molecular Targets and Therapeutic Agents

Abstract

High arsenic (As) levels in food and drinking water, or under some occupational conditions, can precipitate chronic toxicity and in some cases cancer. Millions of people are exposed to unacceptable amounts of As through drinking water and food. Highly exposed individuals may develop acute, subacute, or chronic signs of poisoning, characterized by skin lesions, cardiovascular symptoms, and in some cases, multi-organ failure. Inorganic arsenite(III) and organic arsenicals with the general formula R-As2+ are bound tightly to thiol groups, particularly to vicinal dithiols such as dihydrolipoic acid (DHLA), which together with some seleno-enzymes constitute vulnerable targets for the toxic action of As. In addition, R-As2+-compounds have even higher affinity to selenol groups, e.g., in thioredoxin reductase that also possesses a thiol group vicinal to the selenol. Inhibition of this and other ROS scavenging seleno-enzymes explain the oxidative stress associated with arsenic poisoning. The development of chelating agents, such as the dithiols BAL (dimercaptopropanol), DMPS (dimercapto-propanesulfonate) and DMSA (dimercaptosuccinic acid), took advantage of the fact that As had high affinity towards vicinal dithiols. Primary prevention by reducing exposure of the millions of people exposed to unacceptable As levels should be the prioritized strategy. However, in acute and subacute and even some cases with chronic As poisonings chelation treatment with therapeutic dithiols, in particular DMPS appears promising as regards alleviation of symptoms. In acute cases, initial treatment with BAL combined with DMPS should be considered.

Protective role of HO‐1 against acute kidney injury caused by cutaneous exposure to arsenicals

“…34,35 More than 250 million people worldwide are exposed to unacceptable concentrations of arsenic. 36,37 Here, we demonstrate that a single topical exposure to lewisite, DPCA, DPCYA, or DECA causes their systemic absorption, which is then followed by AKI. The molecular mechanism underlying these effects involves oxidative renal injury.…”

Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development

“…Adverse health effects of As have not been limited to its carcinogenicity [90]. Long-term exposure to iAs, mainly via drinking water, affects almost every organ system in the body, including the brain.…”

Arsenic intoxication: general aspects and chelating agents

“…It is used as a chelator in chronic As poisoning where the signs of arsenicosis are severe, or the patient has complications (Mathieu et al 1992). Currently, the clinical use of this drug is restricted for acute As intoxications to only the initial treatment, because of its toxicity and the necessity of frequent painful parenteral administrations (Nurchi et al 2020). BAL is formulated in peanut oil because of its lipophilic nature and administered intramuscularly at an initial dose of 3-5 mg/kg of body weight every 4 h. This chelating agent demonstrated high systemic distribution and ability to compete effectively with the thiol groups of proteins for binding the As ion (as well as Au, Hg, and Pb), which is then excreted in the urine.…”

“…Measures are urgently required to focus on reduction in As toxicity, early diagnosis, and therapy of As-induced outcomes. Treatment options advocated are chelation therapy, vitamin and mineral supplements, and antioxidant therapy (Nurchi et al 2020;Ratnaike 2003).…”