Chemistry Reference
In-Depth Information
Arsenate
Arsenite
ATG
OH
OH
SG
PNP/
GST
GSH
w
O
V
OH
As
III
As
III
B
HO
OH
GS
SG
2e
-
O
-
SAM
SAM
A
AS3MT
AS3MT
SAHC
SAHC
SG
OH
OH
OH
As
III
O
V
CH
3
O
V
CH
3
As
III
GSH
GS
CH
3
HO
CH
3
O
-
O
-
MMA
V
MADG
MMA
III
MMA
V
OH
GST
w
2e
-
SAM
As
III
AS3MT
A
HO
CH
3
SAHC
MMA
III
AS3MT
SAM
CH
3
CH
3
CH
3
CH
3
SAHC
O
V
CH
3
As
III
As
III
O
V
CH
3
GS
CH
3
GSH
HO
CH
3
O
-
GST
w
O
-
CH
3
DMA
V
DMAG
DMA
III
DMA
V
2e
-
As
III
HO
CH
3
DMA
III
Figure 18.1
Biotransformation of inorganic arsenic into methylated metabolites. Shown are
schemes of the originally proposed, generally accepted, pathway with successive oxidative
methylation and reduction steps (A) and the recently proposed alternative pathway, involving
formation of arsenic-glutathion complexes (B). AS3MT, arsenic (+3 oxidation state) methyl-
transferase; ATG, arsenite triglutathione; DMAG, dimethylarsinic glutathione; GST
w
, glutath-
ione S-transferase
w
; MADG, monomethylarsonic diglutathione; PNP, purine nucleoside
phosphorylase; SAHC, S-adenosylhomocysteine; SAM, S-adenosylmethionine (summarized
from references
2, 23
and
28
)
catalyse conversion of inorganic arsenic to the methylated metabolites enzymati-
cally, are still not fully understood (reviewed in references 23-26). Two possible
metabolic pathways have been postulated, yielding the same methylated metabo-
lites. First a pathway has been proposed with successive oxidative methylation and
reduction steps.
27
Recently, alternative metabolization steps have been discussed,
focusing on glutathione (GSH) conjugation and subsequent methylation
28
(Figure
18.1). Furthermore, recent work suggested that cysteine residues in cellular proteins
might serve an analogous function in complexing the arsenic-containing substrate
like GSH.
29
Whereas biomethylation has long been thought to be a detoxifi cation process,
nowadays it is reasonable to conclude that some adverse health effects seen in
humans chronically exposed to inorganic arsenic are in fact caused by these metabo-
lites. With respect to the trivalent metabolites MMA
III
and DMA
III
, numerous recent
