Mercury - Toxicology of Metals - page 690

of this transporter in the uptake of CH 3 Hg- S -Cys has
also been demonstrated in another study that used cul-
tured endothelial cells from the brain (Mokrzan et al .,
1995). Interestingly, this study measured the uptake
of CH 3 Hg + , as a conjugate of Hcy (CH 3 Hg- S -Hcy) or
as CH 3 Hg- S -Cys and found that these two complexes
were transported similarly. Although the authors of
this study suggest that system L is involved in the
uptake of CH 3 Hg- S -Cys, they did not conclude that
this carrier also mediates the uptake of CH 3 Hg- S -Hcy.
Since these initial studies, two isoforms of the sys-
tem L family have been identifi ed at the molecular
level: the L-type, large neutral amino acid transport-
ers, LAT1 (Kanai et al ., 1998; Prasad et al ., 1999) and
LAT2 (Pineda et al ., 1999). These transporters are
heterodimeric proteins, composed of a heavy chain,
4F2hc, and a light chain, LAT1 or LAT2, bound together
by a disulfi de bond (Chillaron et al ., 2001). With this
knowledge, it has become possible to identify and
characterize further the specifi c mechanisms involved
in the uptake of CH 3 Hg- S -Cys. To illustrate this point,
Simmons-Willis et al . (2002) used oocytes from Xeno-
pus laevis to study directly the involvement of LAT1
and LAT2 in the transport of this conjugate. These
investigators provide the fi rst line of direct molecular
evidence implicating CH 3 Hg- S -Cys as a transportable
substrate of LAT 1 and 2 (Simmons-Willis et al ., 2002).
These data also provide substantive evidence for the
phenomenon of molecular mimicry, where CH 3 Hg- S -Cys
seems to mimic methionine at the site of system L.

it is bound to glutathione (Winroth et al ., 1981). In the
rat kidney, MeHg is bound to a large extent to glutath-
ione (Richardson and Murphy, 1975). The distribution
in the fetus is close to that of the mother, although
fetal brain levels of mercury may be higher (Berlin and
Ullberg, 1963b).

7.1.1.5 Elimination and Excretion
The main routes of elimination of MeHg are through
the liver into the bile and through the kidney into urine.
The net excretion in humans amounts to approximately
1% of the body burden, corresponding to a biological
half-time of 70 days, when this burden is nontoxic
(Swedish Expert Group, 1971). Clinical observations
from MeHg poisoning epidemics in Japan (Swedish
Expert Group, 1971) and Iraq (Bakir et al ., 1973) sup-
port an elimination in man under conditions of intoxi-
cation of the same order of magnitude. The major part
of the excretion is by the fecal route. Much of the MeHg
excreted in the bile is absorbed in the gut, producing an
enterohepatic circulation of MeHg. In the rat, MeHg in
the bile is bound to glutathione and cysteine (Refsvik
and Norseth, 1975). A part of the mercury in the bile
(approximately 30-80%) of the monkey (Berlin et al .,
1975a) is inorganic mercury, derived from the demeth-
ylation of MeHg in the body. This part, less effectively
absorbed in the gut, is excreted. The relative amount of
inorganic mercury in bile may be dose dependent. In
the gut, MeHg can be decomposed by the microfl ora to
inorganic mercury (Rowland et al ., 1977). As inorganic
mercury is absorbed to approximately 5-10%, this
factor contributes to an increased excretion. Approxi-
mately 90% of the total excretion of MeHg in man is by
the fecal route. MeHg is also excreted in breast milk,
the concentration being approximately 5% of the con-
centration in the maternal blood (Bakir et al ., 1973).
Twenty percent of the mercury in breast milk is MeHg,
provided the load of MeHg is nontoxic (Skerfving,
1974a). Bakir et al . (1973) reported 60% MeHg in Iraqi
cases of MeHg poisoning; thus, the fraction of MeHg
excreted in breast milk may be dose-dependent.
MeHg is also taken up in hair during hair formation.
The amount incorporated is proportional to the blood
concentration of mercury at the time of incorporation.
Thus, the ratio of blood concentration/hair concen-
tration in man is 1/250 under steady-state conditions
(Skerfving et al ., 1974; Tsubaki, 1971). The quotient may
vary with age (Suzuki et al ., 1970).
The capacity of MeHg elimination varies in the pop-
ulation. Analyses of consecutive hair segments from
MeHg-exposed populations in Iraq (Al-Shahristani
and Shihab, 1974) suggest that a part (10%) of the pop-
ulation eliminates MeHg at a rate considerably lower
(biological half-time, 110-190 days) than 1% per day.

7.1.1.4 Biotransformation
MeHg undergoes biotransformation to inorganic
mercury by demethylation in the body. Suda and Taka-
hashi (1992) studied the rate of demethylation in the
rat. They found that the reticuloendothelial system is a
site of MeHg demethylation with a dominating role of
spleen and liver. Their results suggest that the demeth-
ylation is accomplished by OH − radicals produced by
P-450 reductase or by HOCl radicals. They also dem-
onstrated that MeHg is taken up and demethylated in
phagocytic cells. (Suda and Hirayama, 1992; Suda et al .,
1993). In the brain, inorganic Hg is slowly accumulated
in astrocytes and microglia after exposure to MeHg.
Considerable levels of inorganic mercury have
been demonstrated in kidney, liver, feces, bile, and
urine after administration of MeHg to primates (Ber-
lin et al ., 1975a, Charleston et al ., 1995). Biotransforma-
tion seems also to occur in the brain at a slow rate.
Studies on Maccaca fascicularis have shown an increas-
ing accumulation of inorganic mercury in astrocytes
and microglia in the brain after long-term exposure
to MeHg (Charleston et al ., 1995). Twenty percent of
MeHg in brain is in water-soluble form, and a part of