Biological Responses to Arsenic Compounds

Arsenic is a metalloid that generates various biological effects on cells and tissues. Depending on the specific tissue exposed and the time and degree of exposure, diverse responses can be observed. In humans, prolonged and/or high dose exposure to arsenic can have a variety of outcomes, including the development of malignancies, severe gastrointestinal toxicities, diabetes, cardiac arrhythmias, and death. On the other hand, one arsenic derivative, arsenic trioxide (As₂O₃), has important antitumor properties. This agent is a potent inducer of antileukemic responses, and it is now approved by the Food and Drug Administration for the treatment of acute promyelocytic leukemia in humans. The promise and therapeutic potential of arsenic and its various derivatives have been exploited for hundreds of years. Remarkably, research focused on the potential use of arsenic compounds in the treatment of human diseases remains highly promising, and it is an area of active investigation. An emerging approach of interest and therapeutic potential involves efforts to target and block cellular pathways activated in a negative feedback manner during treatment of cells with As₂O₃. Such an approach may ultimately provide the means to selectively enhance the suppressive effects of this agent on malignant cells and render normally resistant tumors sensitive to its antineoplastic properties.Arsenic forms complexes with other elements, and it exists in inorganic and organic forms (1–3). The three major inorganic forms of arsenic are arsenic trisulfide (As₂S₃, yellow arsenic), arsenic disulfide (As₂S₂, red arsenic), and arsenic trioxide (As₂O₃, white arsenic) (1–3). There are two different oxidative states of arsenic that correlate with its cytotoxic potential, As(III) and As(V). Among them, As(III) is the most potent form and primarily accounts for its pro-apoptotic and inhibitory effects on target cells and tissues (3). The various forms of arsenic exist in nature primarily in a complex with pyrite (4, 5), although under certain circumstances, arsenic can dissociate from soil and enter natural waters (6), providing a contamination source for humans or animals who ingest such waters. In fact, most associations between long term exposure to arsenic and development of malignancies or other health disorders result from drinking contaminated water, especially in developing countries. Interestingly, pollution of the air with arsenic can also occur under certain circumstances, such as in the case of emissions from coal burning in China (7), providing an additional source of human exposure.The metabolism of arsenic in humans includes reduction to the trivalent state and oxidative methylation to the pentavalent state (reviewed in Ref. 2). There is also reduction of arsenic acid to the arsenous form and subsequent methylation (2). The generation of inorganic or organic trivalent arsenic forms has important implications with regard to the toxicity of this agent, as such compounds are more toxic to the cells and exhibit more carcinogenic properties (2, 3). Thus, many of the consequences of exposure to arsenic as discussed below are the result of the activities and toxicities of the various metabolic products of arsenic compounds. It should be also noted that arsenic has the ability to bind to reduced thiols, including sulfhydryl groups in some proteins (2). Depending on the cellular context, such protein targeting may explain some of its cellular effects and generation of its toxicities and/or therapeutic effects.