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OCR for page 75
Experimental STudies
This chapter discusses the effects of arsenic that have been observed in
experimental studies. It begins with a summary of the experimental studies
described in the 1999 report. Following that summary, toxicokinetic, animal
toxicity, and mechanistic studies of arsenic, published since the previous NRC
report was released, are discussed. This chapter does not provide a compre-
hensive discussion of all the toxicologic mechanisms of arsenic.
SUMMARY OF EXPERIMENTAL STUDIES
DISCUSSED IN THE 1999 REPORT
The previous NBC Subcommittee on Arsenic in Drinking Water reviewed
the data on the toxicokinetics, animal toxicity studies, and mode of action of
arsenic, focusing on the modes of action that might underlie the carcinogenic
effects of arsenic (NRC 1999~. It concluded that inorganic arsenic is readily
absorbed from the gastrointestinal tract in humans and it is mainly transported
in the blood bound to sulfhydryl groups. At low-to-moderate doses, inorganic
arsenic has a half-life in the body of about 4 days and is excreted primarily in
the urine (NRC 19994. Humans and some animals methylate inorganic arsenic
compounds to pentavalent monomethylarsonic acid (MMAV) and pentavalent
dimethylarsinic acid (DMAV), which are less acutely toxic and readily ex-
creted. At the time of the NRC 1999 report, there was little information on the
75
OCR for page 76
76 ARSENIC INDR1rNKING WA TER: 2001 UPDA TE
distribution and toxicity ofthe trivalent methylated metabolites (monomethyI-
arsonous acid AMMAN and dimethylarsinous acid (DMA~. It was noted
that the fractions of the various metabolites of arsenic in urine (inorganic
arsenic, MMA, and DMA) vary markedly among humans, and the toxicoki-
netics of arsenic varies considerably among animal species. It is not known
in which animal species the toxicokinetics more closely resembles that in
humans, and this uncertainty makes it difficult to extrapolate from animals to
humans.
The subcommittee concluded that the mechanisms or modes of action by
which inorganic arsenic causes toxicity, including cancer, is not well estab-
lished (NRC 1999~. The data available on the ability of inorganic arsenic to
act as a cocarcinogen or a tumor promoter in rats and mice are conflicting, but
studies conducted at very high doses indicate that DMA~ is not a tumor initia-
tor but might act as a tumor promoter. Furthermore, inorganic arsenic and its
metabolites have been shown to induce chromosomal alterations (aberrations,
aneuploidy, and sister chromatic exchange) and large deletion mutations, but
not point mutations. Data on other genotoxic responses that might indicate
mode of action for arsenic were not sufficient for conclusions to be drawn.
Therefore, the 1999 subcommittee concluded that "the most plausible and
generalized mode of action for arsenic carcinogenicity is that it induces struc-
tural and numerical chromosomal abnormalities without acting directly with
DNA." The subcommittee also discussed other mechanisms, such as cell
proliferation and oxidative stress. An indirect mechanism of mutagenicity
suggests that the mostplausible shape ofthe carcinogenic dose-response curve
is sublinear "at some point below the level at which a significant increase in
tumors is observed tin the available epidemiological studies]." There was
insufficient scientific evidence to identify the dose at which sublinearity might
occur. Therefore, the subcommittee concluded that "because a specific mode
(or modes) of action has not been identified at this time, it is prudent not to
rule out the possibility of a linear response."
The subcommittee further concluded that arsenicals inhibit some types of
mitochondrial-respiratory function, leading to decreased cellular ATE produc-
tion and increased production of hydrogen peroxide (H2O2) (NRC 1999~.
Those effects could cause the formation of reactive oxygen species, resulting
in oxidative stress. Oxidative stress can have numerous effects, including
inhibition of heme-biosynthetic pathways and induction of major stress pro-
teins. Although the role of arsenic-induced oxidative stress in mediating DNA
damage is not clear, the intracellular production of reactive oxygen species
OCR for page 77
EXPERIMENTAL STUDIES 77
might play an initiating role in the carcinogenic process by producing DNA
damage. In the remainder ofthis chapter, more recent studies on the toxicoki-
netics of arsenic will be discussed, followed by in vitro and in vivo studies
that provide additional information on the mode of action of arsenic.
TOXICOKINETICS
Methylation of Arsenic
.
Arsenic can exist in methylated and inorganic forms as well as in different
valence states (NRC 1999~. The form and valence state can affect the toxicity
of arsenic; therefore, it is important to understand the metabolism and
toxicokinetics of arsenic.
As discussed in the 1999 NRC report, inorganic arsenic is believed to be
methylated via sequential reduction of pentavalent arsenic to trivalent arsenic,
followed by oxidative addition of a methyl group from S-adenosy~methionine
(SAM) to the trivalent form (Figure 3-11. The main products of that methyla-
tion, MMAV and DMAV, are readily excreted in the urine. More recent exper-
iments have detected the presence of the reduced methylated forms EMMA
and DMA~) in human urine.) The development ofthe analytical methods for
the speciation of arsenic metabolites, as well as the advantages and disadvan-
tages ofthese methods, were thoroughly discussed in the previous NRC report
NRC 1999~. The reduced methylated forms and their toxicity are discussed
later in this chapter.
Further methylation of DMA to trimethylarsine is frequently seen in mi-
croorganisms exposed to arsenite ARC 1999~. A smallpercentage of urinary
arsenic as trimethylarsine oxide (TMAO) has been detected in mice, hamsters,
and humans following exposure to DMA (for review, see Kenyon and Hughes
2001), but TMAO or demethylated products of DMA were not detected in the
blood or tissues of mice exposed intravenously to DMA at a dose of 1 or 100
mg/kg (Hughes et al. 2000~. By contrast, TMAO has not been reported to be
present in the urine of mammals exposed to inorganic arsenic. DMA foe
by methylation of inorganic arsenic (Ash) and MMAi~has been shown to clear
'Because trivalent methylated forms of arsenic have been detected only recently, they often
have not been specifically assayed for or discussed in most experiments. In those cases, the
abbreviations MMA and DMA are used without indicating the valence state.
OCR for page 78
78 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
rapidly from cells (Styblo et al. ~999a; Lin et al. 200~). That rapid clearance
might prevent the accumulation of intracellular concentrations of DMA re-
quired for further methylation to TMAO, explaining why TMAO is not de-
tected following exposure to Astir.
Nonenzyrnatic methylation of arsenic has been seen in vitro. Studies have
demonstrated that methy~cobalam~n (a form of vitamin By) can mediate the
nonenzymatic methylation of arsenite (Zakharyan and Aposhian 1999a), but
whether that occurs in viva is not known.
Glutathione (GSH), end possibly other thiols, can act es reducing agents in the
methylation process (NRC 1999~. Recent in vitro studies indicate that dithiols
(e.g., reduced lipoic acid) might be more active than GSH in providing the reduc-
ing environment required for methylation by MA methyTtransferase
(Zakharyan et al. 1999~. Thiol binding might also be involved in arsenic
biotransformation. Trivalent arsenic metabolites are highly bound to cytosolic
proteins in the cells (Styblo and Thomas 1997~. In in vitro studies, protein-bound
inorganic arsenic and MMA were methylated to MMA and DMA, respectively.
It has been proposed that arsenic is bound to a protein dithiol cofactor before the
sequential methylation of arsenic (Thompson 1993; DeKimpe et al. 1999a).
The exact sequence of events in arsenic biotransformation remains urdmown,
but it seems clear that S-adenosy~me~ionine (SAM) is the main source of methyl
H2AsO4-
CH3+
2e~ CH3+ 2e~
AsO33-
CH3AsO32-
Reductase Methyl- MMAV
transferase
2e~
(CH3~2AsO2----------------> (CH3~2AsO
Methyl- DMAV Reductase DMA~i
transferase
CH3ASo2
Reductase MMA~
FIGURE 3-1 Proposed chemical pathway for the methylation of inorganic arsenic
in humans. The enzymes that have been proposed for the reduction and methylation
reactions are indicated. Uncertainties regarding this pathway are discussed in the text.
OCR for page 79
EXPERIMENTAL STUDIES 79
groups for the methylation of arsenic and that the methylation is dependent
upon methyTtransferases. Studies have shown that SAM is required for arsenic
methylation in various in vitro systems and that arsenic methylation in viva
is decreased by specific inhibitors of SAM-dependent methylation and by low
methionine intake ARC 1999~. Because of the importance of SAM in the
methylation of arsenic, much research has been aimed at characterizing the
methyTtransferases involved in SAM-dependent arsenic methylation. During
recent years, arsenite and MMAi~ methyTtransferases from the liver of rabbits,
hamsters, and rhesus monkeys have been purified and partially characterized
(Wilt/fang et al. 1998; Za~aryan et al. 1999~. The Kin,, determined using
Michaelis-Menten kinetics, for arsenite methyTtransferase for hamsters was
~ .79 x ~o-6 M and for MMA methy~transferase was 7.98 x 10- M. The MMA
methy~transferase was higher than the arsenite methyTtransferase. Similar
values were reported for rabbit methy~transferases, but the rhesus monkey had
Knot values for MMA methyTtransferase of 3.5 X 10-6 M and for arsenite
methy~transferase of S.5 x 10-6 M. Zakharyan et al. (1999) reported that the
rabbit liver MMA methyTtransferase had higher affinity for MA than for
MMAV. Furthermore, the Km for MMA~i methyTtransferase from Chang hu-
man hepatocytes was not very different from that of rabbit liver.
The exact structures ofthe arsenic methy~transferases have not been deter-
mined (NRC ~ 999), but recent in vitro studies using rabbit liver cytoso! show-
ed that the two steps in arsenic methylation to DMA are markedly inhibited
by pyrogalloT (0.3 to 9 millimolar) (mM), a specific inhibitor of catechol-O-
methyTtransferase (DeKimpe et al. ~ 999a). Those data suggest that the active
sites of arsenite methyTtransferase and MMA methyTtransferase are similar to
that of catechol-O-methy~transferase. Furthermore, trichIoromethiazide
(TCM), an inhibitor of human microsomal thiopurine methyTtransferase, did
not inhibit the formation of MMA but did inhibit the formation of DMA. in
contrast, neither ofthose arsenic methylation steps was inhibited by an inhibi-
tor of cytosolic thiopurine methy~transferase (p-anisic acid) or by an inhibitor
of cytosine DMA methyTtransferase.
ADMA methy~transferase, which would further methylate DMA forming
TMAO, has not been reported to be present in mammalian cells. Styblo et al.
(1 999b) reported that DMA was the only metabolite detected in rat or human
hepatocytes incubated with DMAV or a glutathione complex of DMA~
(DMAi~-GS).
OCR for page 80
80 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
Species Differences in the Methylation of Arsenic
As discussed in the previous report, there is considerable variation in the
methylation of inorganic arsenic among mammalian species (NRC 1999~.
Rats, mice, and dogs show a very efficient methylation of arsenic to DMA.
Rabbits and hamsters also methylate arsenic relatively efficiently. In most
animals, the DMA that is formed is rapidly excreted in urine. However, in
rats, most of the DMA that is formed accumulates in the red blood cells and
tissues. Rats also appear to methylate administered DMA to TMAO more
efficiently than other species (Kitchin et al. 1999; NRC 1999~. Following
exposure of mate rats to high concentrations of DMA in drinking water (100
mg/L, equivalent to 100,000 )lg/~), about 10% of the urinary arsenic was
present as TMAO (Yoshida et al. 1998~.
Consistent with that marked variation in arsenic methylation efficiency
seen among animal species (Vahter 1999b), the activity of methy~transferases
differs markedly among the animals studied (Healy et al. ~ 999~. The variation
in the activity of those enzymes probably underlies most of the cross-species
variability in methylation ability (for review, see Healy et al. 1999; Vahter
1 999a). Guinea pigs and several types of non-human primates, including the
chimpanzee, seem to be unable to methylate inorganic arsenic (Healy et al.
1999; Vahter ~ 999b), and no methyTtransferase activity was detected in those
species (Healy et al. 1999~.
Human arsenic methy~transferases were Tong thought to be very unstable,
because activity could not be detected in human liver preparations (NRC
~ 999~. Recently, however, arsenic-methylation activity was detected in hu-
man hepatocytes; MMA~imethy~transferase activity was detected in cultured
Chang human hepatocytes (Zakharyan et al. 1999~. Incubation of primary
human hepatocytes with arsenite yielded MMA and DMA, and incubation
with EMMA' produced mainly DMA (Styblo et al. 1999a). Rat hepatocytes,
however, methylated arsenic considerably faster than did human hepatocytes
(Styblo et al. 1999a; Styblo et al. 2000~.
In contrast to humans, most mammals do not excrete appreciable amounts
of MMA in the urine. Recently, however, the Flemish Giant rabbit was found
to excrete substantial amounts of MMA in urine (DeKimpe et al. ~ 999b), and
MMA was formed in vitro after incubation of inorganic arsenic with rabbit-
liver cytosol (DeKimpe et al. 1999a).
No differences, however, were seen in the urinary pattern of arsenic me-
tabolites in three strains of mice 24 hours (fur) after administration of an oral
OCR for page 81
EXPERIMENTAL STUDIES 81
dose of arsenite (Hughes et al. 1999~. More than 95°/O of the arsenic in urine
(corresponding to 60%, 68%, and 69% ofthe administered dose in each ofthe
three mouse strains) was in the form of DMA in all three mouse strains.
As indicated above, the ability to excrete MMA and DMA in the urine
varies among species. Because ofthis variation and other species differences
in arsenic metabolism discussed in this section, extrapolation of data from
studies in animals and animal cells to humans is difficult.
Tissue Differences in the Methylation of Arsenic
The liver appears to play the central role in arsenic methylation (NRC
1999), but in vitro studies using mate mouse cytosoT demonstrated that most
tissues appear to be capable of methylating arsenic (Healy et al. ~998~. The
highest activity of arsenite methyTtransferase was observed in the cytoso! from
the testis, followed by cytosol from the kidney, liver, and lung. More recent
data also point to the liver's important role. Styblo et al. (2000) reported a
much higher rate of arsenic methylation in primary human hepatocytes com-
pared with human keratinocytes and bronchial cells, and no methylation activ-
ity was detected in human urinary-bladder cells. When proliferating human
keratinocytes and bronchial epithelial cells were cultured in the presence of
the relatively Tow arsenite concentration of 0.05 micromolar (EM) (approxi-
mately 3.7 high), more than two-thirds of the cell-associated methylated
arsenic consisted of MMA, most of which was retained intracellularly
throughout a 24-hr incubation. Human keratinocytes cultured in the presence
of ~ EM of methylarsine oxide, a putative substrate for MA methyI-
transferase, did not produce any DMA. Recent studies indicate that EMMA'
might be the most toxic intracellular form of arsenic in terms of oxidative
stress, enzyme inhibition, and DNA `damage (see Mechanistic Data later in this
chapter). It is noteworthy that cells from two tissues that are targets of
arsenic-induced cancer (skin and lung) seem to have less efficient conversion
of MMA to DMA at relevant concentrations of arsenite in culture that is, at
concentrations similar to those that might occur in blood and possibly tissue
following chronic ingestion of low-to-moderate concentrations of arsenic.
However, more studies on this topic are needed before firm conclusions can
be reached.
The situation is even more complex in viva, where the extent of methyla-
tion of inorganic arsenic to MMA and DMA is also influenced by the rate of
OCR for page 82
82 ARSENIC IN DRINKING WATER: 2001 UPDATE
cellular uptake of the inorganic arsenic in the various tissues. Tatum and
Hood (1999) reported that the uptake and methylation of Asset by a kidney-
epithelium-derived cell line, the NKR-52E cell line, were lower than those of
primary rat hepatocytes or hepatoma-derived cell lines. Those data confirm
previous findings that Astir is the main form of arsenic taken up by the liver
(NRC 1999~. In the presence of phosphate-free media, the uptake and
cytotoxicity of AsV in KB oral epidermoid carcinoma cells was greatly en-
hanced (Huang and Lee ~996~.
Cellular uptake and efflux of arsenic vary considerably among the differ-
ent arsenic metabolites, and the variation affects the distribution of metabo-
lites formed in the liver following absorption of arsenic compounds. In com-
parison to the trivalent methylated forms of arsenic, exposure to the pentava-
lent forms (MMAV or DMAV) results in very low tissue concentrations of
MMA and DMA (Hughes and Kenyon 1998; NRC 1999~. That difference is
probably because of a lower cellular uptake and accumulation of the pentava-
lent forms than the trivalent forms. A lower uptake was confirmed in studies
in rat and human hepatocytes that showed a several-fold higher cellular uptake
of Astir and MA than of the corresponding pentavalent forms (Styblo et al.
1999a). In the presence of phosphate-free media, the uptake and cytotoxicity
of AsV in KB oral carcinoma cells were greatly enhanced (Huang and Lee
1996~.
Cellular efflux also appears to vary among the different forms of arsenic.
Styblo et al. (1999a) demonstrated that DMA is the main excretory product in
human and rat hepatocytes. Inhibition of the methylation of MMA to DMA
by increasing arsenite concentrations in the medium resulted in the accumula-
tion of MMA in the cells, indicating that MMA is not excreted as readily from
liver cells as is DMA. Whether that same effect occurs in cells from other
tissues is unknown.
Induction of Arsenic Methy~transferases
The inducibility of arsenic methyTtransferase has been investigated in
mice. Arsenic methyTtransferase activity did not appear to be induced in mice
exposed subchronicly to arsenic in the drinking water (25 or 2,500 Age)
(Hughes and Thompson 1996; Healy et al. 1998~.
OCR for page 83
EXPERIMENTAL STUDIES 83
Trivalent Methylated Arsenic Metabolites
It is obvious from the proposed scheme of arsenic methylation (Figure 3-
1) that pentavalent methylated arsenic compounds can be reduced to trivalent
methylated arsenic compounds EMMA and DMAi~. Although pentavalent
arsenicals can be reduced directly, for example by glutathione (NRC ~ 999),
recent studies indicate the involvement of arsenic reductases. Arsenate reduc-
tase activity has been detected in human liver (Radabaugh and Aposhian
2000~. The enzyme has a molecular weight of about 72 kilodaltons (kI:)a), and
it requires a thiol and a heat-stable cofactor for activity. It did not reduce
MMAV, indicating the presence of two enzymes, arsenate reductase and
MMAVreductase.
MMAV reductase activity has been detected in rabbit liver (Zakharyan and
Aposhian 1999b), hamster tissues (Sampayo-Reyes et al. 2000), and human
liver (Zakharyan et al. 2001~. There is evidence that the human MMAV reduc-
tase is identical to glutathione-s-transferase omega class A. The rabbit liver
MMAV reductase was shown to reduce both DMAV and arsenate (AsV)
(Zakharyan and Aposhian 1999b). The Kn~ values were 2.16 x i0-3 M with
MMAV as the substrate, 20.9 x 10~3 M with DMAV as the substrate, and 109
X i0-3 M with arsenate as the substrate. ~en the Km for the rabbit liver
MMAV reductase was compared with that ofthe As~ methyTtransferase (i.e.,
5.5 x lo-6) and that of MMA~ methyTtransferase (i.e., 9.2 x lo-6), the authors
concluded that MMAV reductase was the rate-limiting enzyme for arsenite
metabolism in the rabbit liver. However, it should be emphasized that, be-
cause of the species differences in arsenic methylation (see above), it is not
known whether the rate-limiting step in the rabbit liver equates to the rate-
limiting step in any particular human organ.
It is not clear to what extent the DMA formed following exposure to
inorganic arsenic is reduced to DMA~'~ by a specific DMAV reductase. The
latter has not been well studied, but DMA~ was detected in the liver of ham-
sters given arsenate (Sampayo-Reyes et al. 2000~. Tn addition, as mentioned
previously, a small percentage of TMAO is found in the urine following expo-
sure to DMA. The formation of TMAO would require the reduction of DMAV
to DMAi~ before the addition of the third methyl group, indicating DMAV
reductase activity.
The activities of the arsenic reductases appear to vary markedly among
tissues. In the male hamster, the highest activity was found in the brain, fol-
lowed by the bladder, spleen, and liver; the Towest activity was found in the
OCR for page 84
84 ARSENIC IN DRINKING WA TER. 2001 UPDA TE
testis (Sampayo-Reyes et al. 2000~. Therefore, the tissues with high arsenic
reductase activity seem to be different from those with high arsenic
methyTtransferase activity (testis > kidney > liver > lung, as discussed previ-
ously). Considering the marked species differences in the metabolism of
arsenic, more data are needed on the tissue variation in arsenic metabolizing
enzymes in various species. In particular, more data are needed on tissue
variations in enzyme activities in humans. More data are also needed on sex
differences, because most experiments have been performed in male animals.
There is increasing evidence that the trivalent methylated arsenic metabo-
lites (especially EMMA are released from the site of arsenic methylation.
Aposhian et al. (2000a) reported that people in Romania exposed to arsenic
in drinking water (28, 84, or 161 PAL) had MA in their urine at concentra-
tions of 5 -7 ,ug/L, irrespective of their exposure. Mandal et al. (2001) re-
ported the presence of both MMAi~ (2-5% of urinary arsenic) and DMA~ (5-
20% of urinary arsenic) in the urine of subjects chronically exposed to inor-
ganic arsenic via drinking water (33-250 ,ug/~) in four villages in West Ben-
gal, India. The concentrations of MMAi~i and DMAi~ in the four villages
ranged from 3-30 ,ug/L and 8-64 vigil, respectively. The concentrations of
both EMMA and DMA~ increased with increasing concentration of total
arsenic in urine (i.e., the sum of metabolites). It should be noted that the
concentrations oftrivaTent metabolites in the urine might have been underesti-
mated, because the trivalent metabolites are easily oxidized (Le et al. 2000~.
On the other hand, the trivalent metabolites are reported to be highly reactive;
therefore, it is unlikely that urinary concentrations of the trivalent metabolites
would be as high as MMAV and DMAV, which are much less reactive and
readily excreted in urine.
There are very few data on the tissue distribution of trivalent methylated
arsenic metabolites following exposure to inorganic arsenic, and no data in
humans. Bile-duct-canulated rats were injectedintravenously with arsenite or
arsenate. Almost 10% ofthe injected dose (50 ~mol/kg) was excreted in the
bile as MMAii~ and Astir (Gregus et al. 2000~. Rats excrete much more arsenic
in the bile than other species; therefore, it is difficult to generalize those re-
sults to other species. However, further support for the formation of trivalent
methylated arsenic compounds in vivo following exposure to inorganic arsenic
comes from experiments in hamsters. Both MMAiii and DMA~i were detected
in the livers of hamsters treated with arsenite (Sampayo-Reyes et al. 2000~.
Some ofthe trivaTentmethylated arsenic metabolites found in urine might
be, in part, the result of reduction occurring in the kidneys and urinary blad-
OCR for page 85
EXPERIMENTAL STUDIES 85
den It has been shown that arsenate is reabsorbed and reduced in the proximal
renal tubuTi, after which Astir is excreted in the urine ARC 1999~. Also, as
mentioned above, high MMAV reductase activity was found in the bladder of
the hamster (Sampayo-Reyes et al.2000), indicating that reduction of MMA,
and possibly also DMA, might occur in the urinary bladder.
Administration of 300 mg ofthe chelating agent sodium 2,3-dimercapto- 1 -
propane sulfonate (DMPS) to people exposed to arsenic in drinking water
(568 ~ 58 vigil) in Inner Mongolia, China, markedly increased the urinary
concentrations of inorganic arsenic (50-125,ug/L, on average) and MMA (50-
325 )lg/~), while the concentration of DMA decreased (240-125 ,ug/~)
(Aposhian et al. 2000a; Le et al. 2000~. This study was the first to identify
MMAi~ in urine as one of the arsenic metabolites. In vitro studies using par-
tially purified rabbit liver MMAi~ methy~transferase showed that the MMAi~-
DMPS complex did not serve as a substrate for the enzyme (Aposhian et al.
2000a). Therefore, the authors suggested that DMPS forms a stable complex
with MA, which is excreted in urine.
It should be noted that the amount of EMMA formed in tissues following
exposure to inorganic arsenic is dependent upon the activity of arsenite
methy~transferase, the enzyme that forms MMAV, and the presence of MMAV
reductase, the enzyme that reduces MMAV to MA. It is also dependent on
the presence and activity of MA methyTtransferase, the enzyme that further
methylates EMMA to DMAV, which is readily excreted from cells (Styblo et
al. 2000~.
Inorganic Asiii and the reduced foes of the methylated arsenic metabo-
lites EMMA and DMA~) are highly reactive and might contribute to the
toxicity observed following exposure to inorganic arsenic (see Mechanisms
of Toxicity). As discussed in the previous NBC report (NRC ~ 999) and by
Styblo et al. (1997), trivalent inorganic and methylated arsenic metabolites
have been shown to complex with GSH. Also, trivalent arsenicals are be-
lieved to forte highly stable complexes with molecules containing vicinal
thiols. In studies investigating the binding of Astir to proteins following expo-
sure to arsenite in human lymphoblastoid cells, at least four 20-50 kDa pro-
teins with arsenic affinity were isolated (Menzel et al. 1999~. Two of the
proteins identified were tubulin and actin. This ability of arsenic to bind to
functional groups (e.g., thiols) can result in the inhibition of certain enzymes
(tin et al.2001) and is one possible mechanism underlying arsenic's toxicity.
Reactions with sulfhydry] groups are also the basis for arsenic detoxification
therapy (e.g., use of DMPS) (Aposhian et al. 2000a).
OCR for page 122
122 ARSENIC IN DRINKING WA TER: 2001 UPDA TE
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Representative terms from entire chapter:
drinking water
