Genetic Toxicology of Arsenic and Antimony

Abstract

Interest in the genetic toxicology of arsenic (As) is motivated by the fact that it is considered as a human carcinogen [1]. The genetic toxicology of arsenicals mainly pertains to that of the trivalent arsenical arsenite (As III ) (Chapter 8) and its trivalent monomethylated and dimethylated metabolites (MMA III and DMA III ) (Chapter 7). The corresponding pentavalent compounds are both less toxic and less genotoxic than the trivalent compounds. This is because the pentavalent compounds are less reactive than the trivalent compounds, which can enter cells more readily than the pentavlent compounds (Chapter 8). Once inside the cell, pentavalent compounds are immediately reduced to trivalent compounds, so the genetic toxicology is attributed to the trivalent species and their products. However, the thioarsenical metabolite dimethyldithioarsinic acid (DMDTA V ), which is pentavalent, shows cytotoxicity and genotoxicty that resembles DMA III rather than DMA V [2]. It must also be kept in mind that some cell lines are able to methylate arsenite. Although hepatocytes are not often used for assessing genotoxicity, rat hepatocytes have a higher rate of methylation than that of human hepatocytes [3]. Insignificant amounts or no methylation was seen in normal human keratinocytes [4], UROtsa cells (SV40-transformed human bladder epithelial line) [3], human lymphoblasts (M. Styblo, personal communication),

Inhibition of nucleotide excision repair by arsenic

“…It is generally considered that inorganic arsenic neither affects DNA directly nor forms adducts with DNA. However, there is mounting evidence that inorganic arsenic and its metabolites may inhibit DNA repair pathways, especially base excision repair (BER) and nucleotide excision repair (NER) [3][4][5][6][7][12][13][14][15], leading to increased cancer risk. Other potential mechanisms for arsenic carcinogenesis/cocarcinogenesis are also under investigation including epigenetic changes by histone modifications, DNA methylation and micro RNA expression elicited by arsenic [7,16,17].…”

Cellular Response of <i>Sinorhizobium</i> sp. Strain A2 during Arsenite Oxidation

“…Arsenite strongly reacts with sulfhydryl groups in proteins and is considered to be more toxic than As(V). Previous studies reported that As induced oxidative stress by generating reactive oxygen species (ROS), which also cause cellular damage ( 10 , 18 , 22 ).…”