Mercury - Toxicology of Metals - page 693

canaliculus depends on GSH (Ballatori and Clarkson,
1982; 1983; 1985a,b; Refsvik, 1982; Refsvik and Norseth,
1975). Indeed, early studies in hepatic tissues indicate
that the preponderance of CH 3 Hg + within hepatocytes
is bound to GSH (Omata et al ., 1978). Magos et al . (1978)
demonstrated that increasing hepatic levels of GSH
enhanced the biliary excretion of GSH and CH 3 Hg + .
In contrast, Refsvik (1978) showed that compounds
that reduce signifi cantly the hepatic and biliary lev-
els of GSH cause the accumulation of CH 3 Hg + in the
liver to decrease. It seems that the intracellular con-
centration of GSH has a signifi cant effect on the trans-
port of CH 3 Hg + . Indeed, studies in mice defi cient in
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2001); however, the exact localization of any one of
them has not yet been determined.

7.1.1.9 Handling of CH 3 Hg + in Placenta
One of the most publicized and serious consequences
of CH 3 Hg + exposure is the deleterious neurological
effect observed in fetuses whose mothers were exposed
to methylmercury during pregnancy (Amin-Zaki et al .,
1974; Harada, 1978; 1995; Inouye and Kajiwara, 1988;
Kajiwara and Inouye, 1986; 1992; Matsumoto et al ., 1965).
CH 3 Hg + crosses the placenta readily and accumulates in
the fetus (Inouye and Kajiwara, 1988; Inouye et al ., 1985;
Suzuki et al ., 1967) and placenta (Ask et al ., 2002) at lev-
els higher than that in maternal tissues and blood. Yet,
little is known about the mechanism(s) by which this
metal is taken up and transported across this organ. Kaji-
wara et al . (1996) have shown that CH 3 Hg + is transported
across the rat placenta by a neutral amino acid carrier in
a time- and dose-dependent manner. These investigators
demonstrated that coinjection with methionine increased
the uptake of CH 3 Hg + . In addition, they proposed that
this increase might be the result of the intracellular con-
version of methionine to Cys, which may subsequently
combine with CH 3 Hg + to form the readily transport-
able conjugate, CH 3 Hg- S -Cys. This conjugate may then
mimic methionine at the site of system L to gain access
to the placenta. Accordingly, the authors concluded that
the neutral amino acid carrier, system L (Kajiwara et al .,
1996), mediated the uptake of CH 3 Hg + in placenta. The
exact species of CH 3 Hg + that was transported was not
determined in this study, nor was there direct evidence
supporting the conclusion that system L was involved
in this transport. However, because system L has been
shown to mediate the transport of CH 3 Hg- S -Cys across
the epithelial cells of and the astrocytes associated with
the blood-brain barrier (Aschner et al ., 1990; Kerper et al .,
1992; Mokrzan et al ., 1995), it is reasonable to postulate
that this same carrier is also responsible for the uptake of
CH 3 Hg- S -Cys in placenta. System L has been identifi ed in
the placenta (Kanai et al ., 1998; Pineda et al ., 1999; Prasad
et al ., 1999) and is an important participant in the transfer
of nutrients from the maternal to the fetal circulation.
It is important to note that a number of other pro-
tein carriers have been identifi ed in the placenta. These
include MRPs, organic anion-transporting polypeptides
(OATPs), OATs, organic cation transporters (OCTs),
and zinc transporters (Leazer and Klaassen, 2003). The
localization of most of these transporters in the placen-
tal membrane has not been determined. However, one
can suggest that one or more of them may play a role in
the uptake and/or effl ux of CH 3 Hg + complexes.
Interestingly, MRP1, 2, and 3 have been identifi ed in
the apical membrane of the syncytiotrophoblast. MRP1

-glutamyltransferase have demonstrated that the
distribution and accumulation of CH 3 Hg + in liver is
affected by the actions of -glutamyltransferase and

cysteinylglycinase (Ballatori et al ., 1998). Furthermore,
experiments in cultured human hepatocytes (HepG2
cells) in which

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-glutamyltransferase was inhibited
indicate that the transport of CH 3 Hg + in these cells
depends on the intracellular concentration of GSH
(Wang et al ., 2000). One can hypothesize that CH 3 Hg-
S -G is formed within the hepatocytes and is subse-
quently transported into the bile at the canalicular
membrane. It is reasonable to hypothesize that CH 3 Hg-
S -G may act as a mimic of GSH at the site of a GSH
transporter in the canalicular membrane of hepato-
cytes. Accordingly, Dutczak et al . (1993) have suggested
that a GSH transport system on the canalicular membrane
serves a primary role in the biliary secretion of CH 3 Hg-
S -G. A GSH-transporter has since been identifi ed on
the canalicular membrane of hepatocytes (Ballatori
and Dutczak, 1994; Ballatori and Truong, 1995;
Fernandez-Checa et al ., 1992; 1993; Garcia-Ruiz et al .,
1992), and it most likely plays a crucial role in the
export of CH 3 Hg + .
After being secreted into the bile, CH 3 Hg + may be
reabsorbed along the biliary tree as a conjugate of GSH
or one of its metabolites, CysGly, and/or Cys (Balla-
tori, 1994). Experimental evidence indicates CH 3 Hg + is
absorbed more readily by ductal epithelial cells when
it is administered as a complex of GSH or Cys (Dutc-
zak et al ., 1991). Once in the biliary tree, CH 3 Hg- S -G
seems to be catabolized to yield CH 3 Hg- S -Cys, which
can be reabsorbed by cells lining the bile ducts and
the enterocytes in the intestine (Dutczak and Ballatori,
1992). Although the actual mechanism(s) involved in
this uptake have yet to be determined, it is reasonable
to hypothesize that CH 3 Hg-Cys acts as a mimic of an
amino acid at the site of an amino acid transporter,
such as system L. A number of amino acid transport-
ers, including system L (LAT3; Babu et al ., 2003), have
been identifi ed in the liver (Bode, 2001; Wagner et al .,

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