Mercury - Toxicology of Metals - page 691

Whether this observation may be due to the existence
of genetic enzyme anomalies in the population or to
other causes is unknown.
Information concerning variations in excretion rate
of MeHg with age is lacking. In newborn mice, the
excretion of MeHg is smaller than after weaning (Choi
et al ., 1981a; Robinson et al ., 1982). This is probably
because before weaning the liver has not acquired the
ability to excrete MeHg bound to glutathione in bile. In
newborn rats this ability is developed during the sec-
ond or fourth week (Ballatori and Clarkson, 1982). It is
likely that the content of the diet can also infl uence the
excretion rate of MeHg through interference with the
reabsorption in the lower part of the intestinal canal.
Landry et al . (1979) showed that in mice, three different
types of diets resulted in considerably different elimi-
nation rates of MeHg.

in the renal cellular uptake and excretion of CH 3 Hg +
indicate that the catabolism of the CH 3 Hg- S -G com-
plex is a necessary step in the renal proximal tubular
absorption of CH 3 Hg + .
Findings from some studies indicate that a fraction
of the CH 3 Hg + that enters into systemic circulation is
oxidized to Hg 2+ either before and/or after it enters the
proximal tubular epithelial cells of the kidney (Dunn
and Clarkson, 1980; Gage, 1964; Norseth and Clarkson,
1970a,b; Omata et al ., 1980; Zalups et al ., 1992). These
fi ndings lead one to suggest that some or all of
the mercuric ions taken up in the kidneys after expo-
sure to CH 3 Hg + may be due to the transport of some
chemical form of Hg 2+ rather than CH 3 Hg + .
Tanaka et al . (1992) demonstrated in mice the exist-
ence of one or more luminal and basolateral mechanisms
involved in the renal tubular uptake of CH 3 Hg + . These
investigators found that the luminal mechanism(s) are
greatly dependent on the actions of

7.1.1.6 Renal Handling of CH 3 Hg +
Although the primary target of CH 3 Hg + is the central
nervous system, it also induces signifi cant deleterious
effects in other organs, including the kidneys (Fowler
1972a,b; Fowler and Woods, 1977; Friberg, 1959; Magos
and Butler, 1976; Magos et al ., 1981; 1985; McNeil et al .,
1988; Norseth and Clarkson, 1970 a,b; Prickett et al .,
1950; Woods and Fowler, 1977; Zalups et al ., 1992).
Until recently, it was unclear as to how this organo-
metal complex is taken up by renal tubular epithelial
cells. Richardson and Murphy (1975) demonstrated
that the renal tubular uptake of CH 3 Hg + depends on
the cellular concentration of GSH. Moreover, several
studies have shown that when CH 3 Hg + is coadminis-
trated with GSH, the renal uptake and accumulation of
CH 3 Hg + increase (Alexander and Aeseth, 1982; Tanaka
et al ., 1992).
It has been proposed that

-glutamyltrans-
ferase. The role of cysteinylglycinase, however, was
not studied. Collectively, their data indicate that the
species of CH 3 Hg + taken up is most likely in the form
of a cysteinylglycine S -conjugate of CH 3 Hg + (CH 3 Hg-
S-CysGly) or CH 3 Hg- S -Cys. The mechanism(s) respon-
sible for the uptake of CH 3 Hg- S -Cys in the proximal
tubule has/have not yet been identifi ed. However, we
can draw parallels from the information available for
the transport of Hg 2+ , as Cys- S -Hg- S -Cys. Inasmuch
as Cys- S -Hg- S -Cys seems to mimic cystine at the site
of an amino acid transporter in proximal tubular cells
(Bridges et al ., 2004), it is possible that CH 3 Hg- S -Cys
behaves in a similar way. In addition, because CH 3 Hg-
S -Cys has been implicated as a molecular mimic of
methionine at the site of system L in endothelial and
glial cells, this complex may also mimic methionine at
the site of one or more carriers of this amino acid in the
kidney.
Uptake of CH 3 Hg + at the basolateral membrane
also seems to involve the multispecifi c carrier, organic
anion transporter 1 (OAT1). As mentioned previously,
in the kidneys, this transporter is localized exclusively
in the basolateral membrane of proximal tubular epi-
thelial cells (Kojima et al ., 2002; Motohashi et al ., 2002).
There is evidence from studies in Xenopus laevis oocytes
implicating this transporter in the cellular uptake of
NAC and DMPS S -conjugates of CH 3 Hg + (CH 3 Hg- S -
NAC and (CH 3 Hg- S) 2 -DMPS, respectively; Koh et al .,
2002). More substantive evidence implicating OAT1
in the basolateral uptake of methylmercuric thiol-con-
jugates comes from recent studies that used MDCK
cells stably expressing hOAT1. The fi ndings from these
studies indicate that NAC, Cys, and Hcy S -conjugates
of CH 3 Hg + are all potential transportable substrates of
OAT1 (Zalups and Ahmad, 2005a,b,c).

γ

-glutamyltransferase and
cysteinylglycinase, which are present in abundance on
the luminal (brush-border) plasma membrane of prox-
imal tubular cells, act on GSH S -conjugates of CH 3 Hg +
(CH 3 Hg- S -G) to yield CH 3 Hg- S -Cys (Zalups, 2000a).
In vitro evidence indicates that the methyl mercuric ion
remains bonded to the sulfur atom of Cys during the
catabolism of GSH (Naganuma et al ., 1988). Experimen-
tal evidence supporting the role of

γ

-glutamyltrans-
ferase in the renal tubular uptake of CH 3 Hg + comes
from studies in which the activity of this enzyme was
inhibited by the alkylating agent acivicin. After the
pretreatment with acivicin, the renal tubular uptake of
CH 3 Hg + was shown to decrease, whereas the urinary
excretion of GSH and CH 3 Hg + was shown to increase
(Berndt et al ., 1985; de Ceaurriz and Ban, 1990; Di Sim-
plicio et al ., 1990; Gregus et al ., 1987; Kostyniak, 1985;
Mulder and Naganuma et al ., 1988; Tanaka et al ., 1990,
1991; 1992; Yasutake et al ., 1989). The observed changes

γ