Arsenic is absorbed into the blood stream at the cellular level and is taken up by
- red blood cells,
- white blood cells, and
- other cells that reduce arsenate to arsenite [Winski and Carter 1995; Wang et al. 1996].
Reduction of arsenate (As V) to arsenite (As III) is needed before methylation can occur. This reaction requires glutathione (GSH) [Miller et al. 2002; Vahter et al. 1983].
A portion of arsenite (As III) is methylated in the liver by enzymatic transfer of the methyl group from S-adenosylmethionine (SAM) to methyl arsonate (MMA V) and dimethyl arsenate (DMA V) [Aposhian et al. 2004; Styblo et al. 2002].
The resulting metabolites are more readily excreted.
Methylation has long been considered the main route of arsenic detoxification, but more recently there has been a growing body of literature supporting other detoxification mechanisms. For example, a number of animal species lack arsenic methylation and excrete inorganic arsenic [Vahter 2002]. The implication is that there may be other more important arsenic detoxification mechanisms in mammals. Other studies have suggested additional detoxification mechanisms such as
- antioxidant defenses,
- resistance to apoptosis, or
- transport [Yoshida et al. 2004].
There have also been studies of arsenic metabolism suggesting that methylation of inorganic arsenic may be a toxification, rather than a detoxification pathway and that trivalent methylated arsenic metabolites, particularly monomethylarsonous acid (MMA III) and dimethylarsinous acid (DMA III), are “unusually capable of interacting with cellular targets such as proteins and DNA” [Kitchin 2001].
Methylation efficiency in humans appears to decrease at high arsenic doses. Patterns of methylated arsenic species in urine are similar between siblings and between siblings and parents, which suggests that arsenic methylation is genetically linked [Chung et al. 2002].
When the methylating capacity of the liver is exceeded, exposure to excess levels of inorganic arsenic results in increased retention of arsenic in soft tissues.
