Trial Information

Folic Acid and Creatine as Therapeutic Approaches for Lowering Blood Arsenic

Approximately 140 million people in over 70 countries are chronically exposed to arsenic
(As)-contaminated drinking water at concentrations far exceeding the World Health
Organization standard of 10 µg/L. As is a carcinogen known to cause cancers of the skin,
bladder, and lung, as well as ischemic heart disease and neurologic impairments. Methylation
of ingested inorganic arsenic (InAs) to methylarsonic-(MMA) and dimethylarsinic acids (DMA)
relies on folate-dependent one carbon metabolism, utilizing S-adenosylmethionine (SAM) as
the methyl donor, and facilitates urinary As elimination. The results from our Nutritional
Influences on Arsenic Toxicity (NIAT) study indicate that folate deficiency and
hyperhomocysteinemia (HHcys) are associated with a reduced capacity to methylate arsenic and
are risk factors for arsenic-induced skin lesions. Furthermore, folic acid (FA)
supplementation does indeed facilitate As elimination and significantly lowers blood As
concentrations in individuals who are folate deficient. We have also determined that blood
As is a good biomarker of As exposure and is directly associated with the risk for
As-induced skin lesions. Collectively, the implication of these findings is that FA has
enormous therapeutic potential for ameliorating the long-term health consequences of arsenic
exposure for the many populations at risk. However, several fundamental questions remain
and will be addressed in this study. This trial is designed to determine 1) whether FA
supplementation lowers blood As concentrations in the general Bangladeshi population, 2) at
what time point a nadir in blood As is achieved, and 3) whether creatine supplementation,
alone or in addition to 400 µg/d FA, will spare methyl groups, resulting in lower blood As,
lower homocysteine (Hcys) concentrations, and increased methylation of As. The creatine
arms are based on multiple studies that show that urinary creatinine concentrations are a
very strong predictor of As methylation. The final step in creatine biosynthesis is the
methylation of guanidinoacetate to creatine; this process consumes 50-75% of all SAM-derived
methyl groups and is also responsible for 50-75% of all Hcys biosynthesis. Thus, this trial
will test the hypothesis that creatine supplementation, which shuts down endogenous creatine
biosynthesis, will spare methyl groups, lower Hcys, and increase As methylation.