Basu et al. (2011) reported the associations of both dietary and blood nutrient measures, as well as urinary creatinine (uCr), with arsenic (As) methyla tion capacity, as assessed by the proportions of urinary inorganic, mono methyl, and dimethyl As metabolites. One finding was that uCr was the strongest predictor of As methylation; participants with higher uCr concentrations had a higher percentage of total urinary As as dimethylarsinic acid (DMA) compared to those with lower uCr. This is consistent with what we have previously reported in Bangladeshi adults and children (Gamble et al. 2005; Ahsan et al. 2007; Hall et al. 2009), and is an interesting and potentially very important observation. Approximately 40% of S-adenosylmethionine (SAM)-derived methyl groups are devoted to the bio synthesis of creatine, the precursor of creati nine (Brosnan et al. 2011; Mudd and Poole 1975). At high levels of As exposure (500–1,000 μg/L), based on one-carbon kinetics (Schalinske and Steele 1989), we estimated that methyla tion of 80% of a daily dose of inorganic As (InAs) to DMA would require approximately 50 μmol SAM, thus consuming approximately 2–4% of the SAM normally turning over in a well-nourished adult per day. Low dietary crea tine intake associated with low-protein or vegetarian diets places an increased demand for SAM for creatine biosynthesis (Brosnan 2011). This could potentially reduce the availability of SAM for As methylation, providing a plausible mechanism under lying this highly reproducible observation. This assumes that uCr reflects, to some extent, dietary creatine intake, as we have observed (Gamble M, unpublished data). Conversely, dietary crea tine intake and/or creatine supplementation downregulates endogenous creatine bio synthesis, potentially sparing SAM for methyla tion of other substrates such as As. We are currently testing this hypothesis in a randomized controlled trial of creatine supplementation. In addition, as Basu et al. (2011) noted, and as we have previously reported (Gamble and Liu 2005), one implication of the observed association between uCr and As methylation capacity is that urinary As should not be expressed per gram creatinine to correct for urine concentration. Rather, uCr should be included as a covariate in regression models.
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