How Does Arsenic Induce Pathogenic Change?
A small molecule that can easily get into cells, arsenic can cause cell injury and death by multiple mechanisms. Interference with cellular respiration explains the potent toxicity of arsenic. In addition, arsine gas may interact directly with red cell membranes. Arsenic is a known human carcinogen, but the specific mechanisms by which it causes cancer are less well understood.
Arsenic toxicity may vary by form.
- Inorganic arsenic is generally more toxic than organic arsenic.
- The type of organic arsenic found in certain seafood (arsenobetaine and arsenocholine) appears to have low toxicity. However, animal studies have shown that other organic arsenic compounds (methyl and phenyl arsenates, for example) can produce health effects similar to those produced by inorganic arsenic [ATSDR 2007].
- In vitro studies have shown that the cellular uptake of As (III) is greater than that of As (V) [Bertolero et al. 1987; Dopp et al. 2004].
- Although there may be some differences in the potency of different chemical forms (e.g., arsenites tend to be somewhat more toxic than arsenates), these differences are usually minor. An exception would be arsine which is highly toxic [ATSDR 2007].
- Metalloid arsenic is generally regarded as nonpoisonous due to its insolubility in water and body fluids.
Although the toxicity of arsenic compounds can vary greatly, in general, a listing of different compounds from highest to lowest toxicity follows:
- inorganic trivalent compounds,
- organic trivalent compounds,
- inorganic pentavalent compounds,
- organic pentavalent compounds, and
- elemental arsenic [Gorby 1988].
Two mechanisms of arsenic toxicity that impair tissue respiration are described below.
- Arsenic binds with sulfhydryl groups and disrupts sulfhydryl containing enzymes; As (III) is particularly potent in this regard. As a result of critical enzyme effects, there is
- inhibition of the pyruvate oxidation pathway and the tricarboxylic acid cycle,
- impaired gluconeogenesis, and
- reduced oxidative phosphorylation.
- Another mechanism involves substitution of As (V) for phosphorus in many biochemical reactions.
- Arsenite does not compete with phosphate, but tends to bind to dithiol groups.
- Replacing the stable phosphorus anion in phosphate with the less stable As (V) anion leads to rapid hydrolysis of high energy bonds in compounds such as ATP, a process that leads to loss of high energy phosphate bonds and effectively “uncouples” mitochondrial respiration [Rossman 2007].
Arsenic’s affinity for thiol groups allows for the use of thiol group-containing chelators in the treatment of acute arsenic poisoning.
- Arsenite binds specifically to thiol group-containing hormone receptors, a process that prevents the binding of steroids [Lopez et al. 1990; Kaltreider et al. 2001].
- It is hypothesized that arsenic’s diabetogenic effect may be related to its ability to bind and inhibit the insulin receptor [Rossman 2007].
The present view of arsenic carcinogenesis is that there are many possible chemical forms of arsenic that may be causal in carcinogenesis. In addition, arsenic induced carcinogenesis may have different mechanisms in different tissues with contributions from all species present in that tissue [ROM 2007]. Some studies in arsenic metabolism suggest that methylation of inorganic arsenic may be a toxification, rather than a detoxification pathway and that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid and dimethylarsinous acid, have a great deal of biological activity [Kitchin 2001]. The evidence indicates that trivalent, methylated, and relatively less ionizable arsenic metabolites may be capable of interacting with cellular targets such as proteins and even DNA [Kitchin 2001].
A scientific consensus has not yet been reached on the many suggested modes of arsenic carcinogenesis that exist in the literature. These include modes that are predominately genotoxic (i.e., chromosomal abnormalities, oxidative stress, and gene amplification) vs. more nongenotoxic (i.e., altered growth factors, enhanced cell proliferation and promotion of carcinogenesis, and altered DNA repair). Likewise, the dose-response relationship at low arsenic concentrations for any of these suggested modes is not known [Kitchin 2001].
Arsine gas poisoning results in a considerably different syndrome from that caused by other forms of arsenic. After inhalation, arsine rapidly binds to red blood cells, producing irreversible cell membrane damage.
- At low levels, arsine is a potent hemolysin, causing dose-dependent intravascular hemolysis.
- At high levels, arsine produces direct multisystem cytotoxicity.
- Arsenic binds with sulfhydryl groups and disrupts sulfhydryl containing enzymes.
- It replaces the stable phosphorus anion in phosphate with the less stable As (V) anion, leading to rapid hydrolysis of high energy bonds in compounds such as ATP.
- The type of organic arsenic found in certain seafood appears to have low toxicity.
- Studies suggest arsenic detoxification pathways other than methylation may be more important.
- There is no scientific consensus on mode of arsenic carcinogenesis.
- A dose response relationship at low arsenic concentrations for carcinogenesis is not known.
- Arsine gas binds to red blood cells, causing hemolysis.