Cadmium and Kidneys: Low-Level Exposure and Effects in Women

water with elevated concentrations of arsenic, a potent human carcinogen. It is well established that chronic exposure to As is associated with skin, lung, and bladder cancers Inorganic As (iAs) is metabolized by reduction of pentavalent iAs to trivalent, followed by oxidative methylation to monomethylated As (MMA), further reduction from pentavalent MMA to trivalent, and at last methylation to dimethylated As (DMA) (Vahter 2002). Not all of the As is fully methylated and some As remains as iAs and MMA, which are eliminated in the urine along with DMA. In vitro studies have shown that the trivalent forms, particularly monomethylarsonous acid (MMA III), are generally more toxic than the pentavalent forms (Nesnow et al. 2002; Styblo et al. 2000; Vega et al. 2001). Thus, the observed large variability in the distribution of metabolites in urine among individuals and population groups might be associated with differences in tissue distribution and retention of toxic metabolites (Vahter 2002). This, in turn, is likely to lead to variation in susceptibility. A number of studies indicate that increased percentage of MMA (%MMA) and decreased percentage of DMA (%DMA) in urine are associated with an increase in As retention in the body (Vahter 2002) and an increase of Part of the interindividual variation in As metabolism may be due to environmental factors, but earlier studies have shown that hereditary differences are very likely to contribute (Chung et al. 2002; Vahter 2000). So far, knowledge on these genetic factors and their mechanisms is very limited. Recent findings from small-scale studies indicate that polymorphisms in glutathione S-transferase (GST) omega 1 (GSTO1), which encodes an enzyme that can reduce pentavalent As species, might be related to enzyme activity and patterns of methylated As metabolites (Marnell et al. 2003; Tanaka-Kagawa et al. 2003). A few studies have indicated that two other GSTs, GST mu 1 (GSTM1) and GST theta 1 (GSTT1), have minor effects on As metabolism as well (Chiou et al. 1997; Marcos et al. 2006). In another study, involving a Mexican population, arsenic(+III)methyl-transferase (AS3MT; also labeled CYT19), which is known to methylate trivalent As, was found to have three intronic single nucleotide polymorphisms (SNPs) that were significantly related to DMA/MMA ratios. However, this association was only valid for children (Meza et al. 2005). S-Adenosyl-methionine (SAM) is the methyl donor for methylation of As (Marafante et al. 1985), and polymorphisms in genes involved in SAM metabolism (i.e., one-carbon metabolism), …