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Metallothionein, cadmium, copper and zinc levels of human and rat tissues
Toxicology Letters, 38 (1987) 205-211
205
Elsevier
TXL 01855
METALLOTHIONEIN,
CADMIUM,
COPPER
AND ZINC LEVELS OF
HUMAN AND RAT TISSUES (Metallothionein;
metal distribution;
H.E.
G.A.
HEILMAIERa,
DRASCHb,
metal binding; species differences)
E. KRETSCHMERb
and K.H.
SUMMER”
“Instrtute of Toxicology, Gesellschaft fur Strahlen- und Umweltforschung Mtinchen, ,Veuherberg, and ‘Institute of Forensic Medicine, University of Munich, Munich (F. R. G.) (Received
21 April
(Revision
received
22 May 1987)
1987)
(Accepted
4 June
1987)
SUMMARY Metallothionein heart,
kidney
autopsies
(MT), zinc (Zn), copper
cortex,
liver, lung,
(10 male individuals,
muscle,
of MT in the human
kidney cortex,
respectively.
Positive
cortex
human
linear relationships
and MT in human
samples
varied
In most tissues human
kidney
between
all smokers)
between
in 10 tissues (brain,
spleen and stomach) and Wistar
3.8 and 495 ag/g
those of rats about
from
human
rats. The mean tissue
wet weight in spleen and
MT levels were high as compared
MT levels exceeded
were observed
(Cd) were determined
small intestine,
mean age 43 + 9 years,
concentrations
in liver and kidney
(Cu) and cadmium pancreas,
to rats; particularly
2% and IO-fold,
Zn or Cu and MT in human
respectively.
liver and between
Cd
cortex.
INTRODUCTION
Metallothionein (MT), a low molecular weight protein with high cysteine and metal content [1,2], binds both essential (Zn, Cu) and non-essential metals (Cd, Hg). In view of the ability of MT to be induced by metals, the protein plays a crucial
Address for correspondence: Dr. Karl H. Summer, Institut und Umweltforschung, D-8042 Neuherberg, F.R.G. Abbreviations: troscopy;
Cd, cadmium;
ICP-AES,
03784274/87/$
03.50
atomic
0
Cu, copper;
fur Toxikologie,
MT, metallothionein;
emission
spectroscopy
1987 Elsevier
Science
Zn, zinc; AAS, atomic
with inductively
Publishers
Gesellschaft
coupled
B.V. (Biomedical
plasma
Division)
fur Strahlen-
absorption excitation.
spec-
role in the homeostasis and toxicity of metals f3,4]. The biological activity of metals thus is determined by both the concentration in the tissue and the fraction bound to MT. However, there are few reports as to the MT concentrations in human tissues. In a previous study we found high MT levels in human kidney cortex, which were even higher in smokers [S]. In these kidney cortices the amount of cadmium bound to MT directly correlated with the content of renal cadmium but not with zinc or copper. In a recent study Onosaka et al. [6] reported similarly high MT levels in human river and a strong positive reIationship between hepatic Zn and MT concentrations. To further elucidate the relationship between tissue levels of MT and metals, we investigated in this study the levels of MT, zinc, copper and cadmium in 10 different organs from human autopsies and rats. Some of the rat data have been previously reported 17f. MATERIALS
AND METHODS
Samples of human tissues were obtained from 10 male individuals (20-SO years old, mean age 43 f 9, all smokers) necropsied within 2 days after sudden death. None of the individuals received medication before death. Samples were stored at -80°C until being processed further. Tissues of humans and rats (Wistar strain, males, 180-200 g, from the GSF stock N~uherberg) were homogenized with a Potter-El~ehjem or Ultra-Turrax in 4 or 9 ~01s. of 30 mM Tris-HCf buffer pH 7.4, and subsequently centrifuged at 18 000 x g. MT was determined in the supernatants by a modified cadmium saturation method as described previously ]7]. Zn, Cu and Cd were detected in tissue homogenates by atomic emission spectroscopy with inductively coupled plasma excitation [8] or atomic absorption spectroscopy after wet ashing of the samples at 140°C with nitric acid 191. RESULTS
MT was detected in all human tissues investigated (Fig. 1). The highest MT tissue levels were found in kidney cortex. In all tissues except brain and small intestine, human samples showed higher MT levels than those of rats. Particularly in liver and kidney, human MT levels exceeded those of rats about 25- and lo-fold, respectively. Tissue concentrations of Zn, Cu and Cd are shown in Fig. 2. Human tissues showed moderate differences in their Zn or Cu levels whereas regarding Cd Ievels pronounced variations were observed. The highest Cd concentrations (29.7 + 13.6 @g/g .I wet weight) were observed in the kidney cortex. In most human and rat tissues the levels of Zn and Cu were apprfjximately similar within a factor of 2, In comparison with the very low levels of Cd in rat tissues, the Cd levels of all human tissues were remarkably higher. The Cd levels of all rat tissues were lower than the detection limit of 20 ng Cd/g tissue wet weight. In
207
600,
Faman gj
400
fat
5 i 0
200
: .!? WI -
80 CI a
.c0 ; ._ c 0 = IO z E
60
40
20
pencreas
Fig. 1. Metallothionein from male individuals nein was determined as means
f
liver
muscle bnrt kidney *me” brain stomech intestine
concentrations
epleen
of 10 tissues of man and rat, respectively.
within 2 days after sudden by the cadmium
lung
saturation
Samples
were obtained
death (n = 10) and male Wistar
rats (n =6). Metallothio-
assay as previously
[7]. Values are expressed
described
SD.
human liver, positive relationships between the concentrations of both Zn and Cu and the amount of MT were observed. The regression coefficients were r = 0.871 (MT @g/g) = 9.8 Zn @g/g) - 257) and r = 0.955 (MT @g/g) = 100 Cu @g/g) - 359), respectively (Fig. 3a,b). In human kidney cortex, a positive relationship was observed between Cd and MT with a regression coefficient of r = 0.779 (MT &g/g) = 13.4 Cd @g/g) + 98.5) (Fig. 3~). Metallothionein levels in human kidney and liver were not significantly correlated (Fig. 4).
208
pancreas
liver
Fig. 2. Zinc, copper obtained
ktdney sma”
nWscle heart intestinebrain stomach
and cadmium
from male individuals
Metals were determined
concentrations within
by ICP-AES
spleen
of 10 tissues of man and rat, respectively.
2 days after sudden
death
or AAS after wet ashing
of the rat tissues were lower than the detection as means
lung
(n = 10) and male Wistar
of the samples
limit of 20 ng Cd/g
Samples
were
rats (n = 6).
with nitric acid. Cd levels
tissue wet weight.
Values are expressed
+ SD.
DISCUSSION
MT was detected in all rat and human tissues investigated. The rat data confirm earlier findings of us [7] and others [lo], although lower levels of brain MT were obtained with a radioimmunoassay [ 111. In most human tissues higher levels of MT were observed than in rats. Moreover, human MT levels, particularly in liver and kidney showed greater interindividual variations, e.g., the concentrations of human hepatic MT varied between 11 and 1000 pg/g. The extraordinarily high levels of MT
750-
b
a
C
l
,/
I’
I’
l,’ ,’
,’
,’
,’
#’
/’ 0
,’
750
500. ,’
/ ,’
,i
500
#’
4*
,A’
250
,’
0
,’
,’
250-
0,’
9,s
.’
,’
,’
4 /’ I’ #’ ’ #’
,I *’
/’
,’
0
4,’
l
,,A
l
,/
,’
_
l
4
-0
d.0
25
50
75
100
2.5
5
Zn Cpg/g
Fig. 3. Relationship
between
mium and metallothionein were determined
7.5
10
12.5
10
zinc and copper in human
as described
in Materials
tissue
cortex
30
40
w.wt.1
and metallothionein
kidney
20
Cd
cu
in human
liver (a,@ and between
(c). Metals and metallothionein
in autopsy
cad-
samples
and Methods.
in human kidney and liver may reflect a different transcriptional control of the protein, the occurrence of multiple subtypes of human MT isoforms [12], or the high exposure of man to environmental metals. In accordance with the latter, levels of zinc, copper and particularly cadmium in human liver and levels of zinc and cadmium in human kidney clearly exceeded those of the rat. With a ratio of 7 mol Cd per mol of MT, MT of human liver and kidney cortex has the capacity to bind total tissue cadmium. This supports the assumed protective
;
t E
1:
Fig. 4. Relationship tained
250
metsllothmne~n
between
from male individuals
by the cadmium
saturation
500 in
liver
750 C pg
I g
metallothionein
1000
tossue
w. wt.1
levels in human
within 2 days after sudden assay as previously
described
death [7].
liver and kidney cortex. (n = IO). Metallothionein
Samples
were ob-
was determined
210
role of MT in the detoxification of Cd. However, in the renal cortex of both smokers and non-smokers, MT was shown to bind about 50% of tissue Cd only [5]. The remaining non-MT Cd may represent a significant toxic potential. Zinc, copper and cadmium are potent inducers of MT in animal tissues [ 131. Although there is no clear evidence for the induction of MT by these metals in human tissues, the present findings on positive correlations between renal MT and cadmium, and hepatic MT and zinc support this view. Similarly, a close relationship between renal MT and tissue cadmium of smokers and non-smokers [5] and a positive correlation between MT and zinc in human liver [6,14] have been observed. These data indicate that MT in human kidney is mainly induced by cadmium whereas in liver it may be preferentially induced by zinc and possibly copper. However, since induction of MT has also been reported after various stresses [15,16], factors like the hormonal [17,18] and nutritional [19] status and even the type of death [20] might contribute as well. As shown in Fig. 4, there seems to be no correlation between hepatic and renal MT levels which we have also observed in a recent investigation with 145 postmortem samples of liver and kidneys [20]. Except in 2 individuals, MT levels in human kidney cortex exceeded those of the liver. However, in these cases hepatic Zn and renal Cd levels were more than twice and less than 50% of the average values, respectively. This supports the relevance for MT induction of the high Cd content of the kidney as compared to the liver, In contrast, MT levels of rat liver and kidney positively correlated with each other either after acute or subchronic exposure to cadmium and zinc or the acute administration to iodoacetate (unpublished observation). Therefore the chronic exposure of man to low levels of metals, in particular cadmium, and the preferential distribution of Cd-MT into the kidney may explain the observed lack of correlation. In conclusion, these results demonstrate that considerable amounts of MT are present in various human tissues. The particularly high levels of MT in human liver and kidney also in comparison to rats and the high levels of metals in these tissues suggest that the expression of MT in human tissues may respond to environmental factors, especially chronic low level exposure to metals. ACKNOWLEDGEMENTS
The authors wish to thank Dr. P. Schramel, GSF, Chemie, for the metal determinations and Mrs. M. Ederer ger for expert technical assistance. Part of this work was presented at the 4th International ment Analytical Chemistry in Medicine and Biology, F.R.G.
Institut fur ijkologische and Mr. J. LichtmannegWorkshop on Trace EleApril 1986, Neuherberg,
211
REFERENCES J.H.R.
Kagi and M. Nordberg
E.C. Foulkes
(Ed.),
R.J. Cousins,
5 K.H.
G.A.
influence
Drasch
and H.E.
of smoking,
(Ed.),
Hum.
and K.I. Yamamoto,
with iodoacetic
8 P. Schramel, Nachweis Anal.
Heilmaier,
Toxicol.,
acid and zinc, Arch.
A. Wolf,
biologischem
Material,
S.I. Tashiro,
by cadmium Schmidt
13 D.L.
and cadmium
1. Shimizu,
of metallothionein
and Biology in human
M. Furuta,
and metals
of
kidney
T. Yasutomi,
in malignant
38 (1986) 261-268. content and zinc status in various
Toxicol.,
and
tissues of rats
56 (1985) 247-251.
Die Leistungsfahigkeit
R. Seif and Presenius
and M.G. Cherian,
to metals.
expression,
Biochemistry
195-266.
der ICP-Emissionsspektroskopie
in biologisch-medizinischen
I. Effect
und
in Umweltproben,
and D.H.
Hamer,
Eaton,
N.H.
Anal.
zum
Fresenius
Z.
Stacey,
K.L.
Wong
indicator
von
tissues of rat in 22 (1981) 91-101.
in tissues by radioimmunoassay
and
154 (1986) 213-223.
and an effect of rus on human
metallothionein
gene
83 (1986) 3346-3350.
and C.D.
glutathione,
Klaassen,
Dose-response
heme oxygenase
Pharmacol., 55 (1980) 393-402. 14 J. Chung, N.O. Nartey and M.G. Cherian, - A potential
in various
salts, Toxicology,
of metallothionein
Sci. U.S.A.,
ions on rat liver metallothionein,
of metallothionein
of cadmium
Biochem.,
zur Druckveraschung
302 (1980) 62-64.
synthesis
injection
Cell specificity
Acad.
Eine neue Apparatur
Chem.,
Determination
method,
Natl.
Klose,
The induced
saturation Proc.
B.J.
Z. Anal.
of repeated
11 C.V. Nolan and Z.A. Shaikh, 12 C.J.
1982. Metab.
310 (1982) 209-216.
9 P. Schramel,
response
The Chemistry,
Metallothionein
K. Tanaka,
B.J. Klose and S. Hasse,
10 S. Onosaka
J. Inherit.
5 (1986) 27-33.
Concentrations
von Spurenelementen
Chem.,
New York,
and zinc metabolism,
1979, pp.
non-malignant tissues in human liver, Toxicology, 7 H.E. Heilmaier and K.H. Summer, Metallothionein treated
Base& 1979.
ElsevierINorth-Holland,
to copper
New York,
K.S. Min, C. Fukuhara,
K. Kobashi
related
in M. Webb
Elsevier/North-Holland,
6 S. Onosaka,
Birkhauser,
1) (1983) 15-21.
Summer,
cortex:
- aspects
The metallothioneins,
Cadmium,
Metallothionein,
Roles of Metallothionein,
Metallothionein
Dis., 6 (Suppl. 4 M. Webb,
(Eds.),
Biological
Metallothionein
of environmental
exposure
effects
and cytochrome
of various
metal
P-450, Toxicol.
Appl.
levels in liver and kidney of Canadians
to cadmium,
Arch.
Environ.
Health,
41 (1986)
319-323. 15 S.H. Oh, J.T. Deagen, Its induction
by various
16 F.N. Kotsonis agents,
P.D.
and C.D. Klaassen,
Toxicology,
synergistic
action
Effect
Cousins,
Biological
function
of metallothionein.
V.
234 (1978) E282-E285.
in hepatic
metallothionein
in rats treated
with alkylating
E. Kretschmer,
and norepinephrine
Dietary
of rats,
on zinc thionein
levels and in-
247 (1984) E318-E322. regulation
and glucocorticoids,
Revis and T.R. Osborne, Drasch,
Weswig,
of epinephrine
Hormonal
of glucagon
tion in the liver and kidney 20 G.A.
Increase
in rat liver, Am. J. Physiol.,
18 K.R. Etzel and R.J. 19 N.W.
and P.H.
Am. J. Physiol.,
51 (1979) 19-27.
17 F.O. Brady and B. Helvig, duction
Whanger
stresses,
protein
Environ.
P. Neidlinger
of liver metallothionein Proc.
effects Health
and K.H.
zinc: independent
Sot. Exp. Biol. Med., on cadmium
Perspect., Summer,
and metallothionein
54 (1984) 83-91. submitted
and
167 (1981) 233-236.
for publication.
accumula-
205
Elsevier
TXL 01855
METALLOTHIONEIN,
CADMIUM,
COPPER
AND ZINC LEVELS OF
HUMAN AND RAT TISSUES (Metallothionein;
metal distribution;
H.E.
G.A.
HEILMAIERa,
DRASCHb,
metal binding; species differences)
E. KRETSCHMERb
and K.H.
SUMMER”
“Instrtute of Toxicology, Gesellschaft fur Strahlen- und Umweltforschung Mtinchen, ,Veuherberg, and ‘Institute of Forensic Medicine, University of Munich, Munich (F. R. G.) (Received
21 April
(Revision
received
22 May 1987)
1987)
(Accepted
4 June
1987)
SUMMARY Metallothionein heart,
kidney
autopsies
(MT), zinc (Zn), copper
cortex,
liver, lung,
(10 male individuals,
muscle,
of MT in the human
kidney cortex,
respectively.
Positive
cortex
human
linear relationships
and MT in human
samples
varied
In most tissues human
kidney
between
all smokers)
between
in 10 tissues (brain,
spleen and stomach) and Wistar
3.8 and 495 ag/g
those of rats about
from
human
rats. The mean tissue
wet weight in spleen and
MT levels were high as compared
MT levels exceeded
were observed
(Cd) were determined
small intestine,
mean age 43 + 9 years,
concentrations
in liver and kidney
(Cu) and cadmium pancreas,
to rats; particularly
2% and IO-fold,
Zn or Cu and MT in human
respectively.
liver and between
Cd
cortex.
INTRODUCTION
Metallothionein (MT), a low molecular weight protein with high cysteine and metal content [1,2], binds both essential (Zn, Cu) and non-essential metals (Cd, Hg). In view of the ability of MT to be induced by metals, the protein plays a crucial
Address for correspondence: Dr. Karl H. Summer, Institut und Umweltforschung, D-8042 Neuherberg, F.R.G. Abbreviations: troscopy;
Cd, cadmium;
ICP-AES,
03784274/87/$
03.50
atomic
0
Cu, copper;
fur Toxikologie,
MT, metallothionein;
emission
spectroscopy
1987 Elsevier
Science
Zn, zinc; AAS, atomic
with inductively
Publishers
Gesellschaft
coupled
B.V. (Biomedical
plasma
Division)
fur Strahlen-
absorption excitation.
spec-
role in the homeostasis and toxicity of metals f3,4]. The biological activity of metals thus is determined by both the concentration in the tissue and the fraction bound to MT. However, there are few reports as to the MT concentrations in human tissues. In a previous study we found high MT levels in human kidney cortex, which were even higher in smokers [S]. In these kidney cortices the amount of cadmium bound to MT directly correlated with the content of renal cadmium but not with zinc or copper. In a recent study Onosaka et al. [6] reported similarly high MT levels in human river and a strong positive reIationship between hepatic Zn and MT concentrations. To further elucidate the relationship between tissue levels of MT and metals, we investigated in this study the levels of MT, zinc, copper and cadmium in 10 different organs from human autopsies and rats. Some of the rat data have been previously reported 17f. MATERIALS
AND METHODS
Samples of human tissues were obtained from 10 male individuals (20-SO years old, mean age 43 f 9, all smokers) necropsied within 2 days after sudden death. None of the individuals received medication before death. Samples were stored at -80°C until being processed further. Tissues of humans and rats (Wistar strain, males, 180-200 g, from the GSF stock N~uherberg) were homogenized with a Potter-El~ehjem or Ultra-Turrax in 4 or 9 ~01s. of 30 mM Tris-HCf buffer pH 7.4, and subsequently centrifuged at 18 000 x g. MT was determined in the supernatants by a modified cadmium saturation method as described previously ]7]. Zn, Cu and Cd were detected in tissue homogenates by atomic emission spectroscopy with inductively coupled plasma excitation [8] or atomic absorption spectroscopy after wet ashing of the samples at 140°C with nitric acid 191. RESULTS
MT was detected in all human tissues investigated (Fig. 1). The highest MT tissue levels were found in kidney cortex. In all tissues except brain and small intestine, human samples showed higher MT levels than those of rats. Particularly in liver and kidney, human MT levels exceeded those of rats about 25- and lo-fold, respectively. Tissue concentrations of Zn, Cu and Cd are shown in Fig. 2. Human tissues showed moderate differences in their Zn or Cu levels whereas regarding Cd Ievels pronounced variations were observed. The highest Cd concentrations (29.7 + 13.6 @g/g .I wet weight) were observed in the kidney cortex. In most human and rat tissues the levels of Zn and Cu were apprfjximately similar within a factor of 2, In comparison with the very low levels of Cd in rat tissues, the Cd levels of all human tissues were remarkably higher. The Cd levels of all rat tissues were lower than the detection limit of 20 ng Cd/g tissue wet weight. In
207
600,
Faman gj
400
fat
5 i 0
200
: .!? WI -
80 CI a
.c0 ; ._ c 0 = IO z E
60
40
20
pencreas
Fig. 1. Metallothionein from male individuals nein was determined as means
f
liver
muscle bnrt kidney *me” brain stomech intestine
concentrations
epleen
of 10 tissues of man and rat, respectively.
within 2 days after sudden by the cadmium
lung
saturation
Samples
were obtained
death (n = 10) and male Wistar
rats (n =6). Metallothio-
assay as previously
[7]. Values are expressed
described
SD.
human liver, positive relationships between the concentrations of both Zn and Cu and the amount of MT were observed. The regression coefficients were r = 0.871 (MT @g/g) = 9.8 Zn @g/g) - 257) and r = 0.955 (MT @g/g) = 100 Cu @g/g) - 359), respectively (Fig. 3a,b). In human kidney cortex, a positive relationship was observed between Cd and MT with a regression coefficient of r = 0.779 (MT &g/g) = 13.4 Cd @g/g) + 98.5) (Fig. 3~). Metallothionein levels in human kidney and liver were not significantly correlated (Fig. 4).
208
pancreas
liver
Fig. 2. Zinc, copper obtained
ktdney sma”
nWscle heart intestinebrain stomach
and cadmium
from male individuals
Metals were determined
concentrations within
by ICP-AES
spleen
of 10 tissues of man and rat, respectively.
2 days after sudden
death
or AAS after wet ashing
of the rat tissues were lower than the detection as means
lung
(n = 10) and male Wistar
of the samples
limit of 20 ng Cd/g
Samples
were
rats (n = 6).
with nitric acid. Cd levels
tissue wet weight.
Values are expressed
+ SD.
DISCUSSION
MT was detected in all rat and human tissues investigated. The rat data confirm earlier findings of us [7] and others [lo], although lower levels of brain MT were obtained with a radioimmunoassay [ 111. In most human tissues higher levels of MT were observed than in rats. Moreover, human MT levels, particularly in liver and kidney showed greater interindividual variations, e.g., the concentrations of human hepatic MT varied between 11 and 1000 pg/g. The extraordinarily high levels of MT
750-
b
a
C
l
,/
I’
I’
l,’ ,’
,’
,’
,’
#’
/’ 0
,’
750
500. ,’
/ ,’
,i
500
#’
4*
,A’
250
,’
0
,’
,’
250-
0,’
9,s
.’
,’
,’
4 /’ I’ #’ ’ #’
,I *’
/’
,’
0
4,’
l
,,A
l
,/
,’
_
l
4
-0
d.0
25
50
75
100
2.5
5
Zn Cpg/g
Fig. 3. Relationship
between
mium and metallothionein were determined
7.5
10
12.5
10
zinc and copper in human
as described
in Materials
tissue
cortex
30
40
w.wt.1
and metallothionein
kidney
20
Cd
cu
in human
liver (a,@ and between
(c). Metals and metallothionein
in autopsy
cad-
samples
and Methods.
in human kidney and liver may reflect a different transcriptional control of the protein, the occurrence of multiple subtypes of human MT isoforms [12], or the high exposure of man to environmental metals. In accordance with the latter, levels of zinc, copper and particularly cadmium in human liver and levels of zinc and cadmium in human kidney clearly exceeded those of the rat. With a ratio of 7 mol Cd per mol of MT, MT of human liver and kidney cortex has the capacity to bind total tissue cadmium. This supports the assumed protective
;
t E
1:
Fig. 4. Relationship tained
250
metsllothmne~n
between
from male individuals
by the cadmium
saturation
500 in
liver
750 C pg
I g
metallothionein
1000
tossue
w. wt.1
levels in human
within 2 days after sudden assay as previously
described
death [7].
liver and kidney cortex. (n = IO). Metallothionein
Samples
were ob-
was determined
210
role of MT in the detoxification of Cd. However, in the renal cortex of both smokers and non-smokers, MT was shown to bind about 50% of tissue Cd only [5]. The remaining non-MT Cd may represent a significant toxic potential. Zinc, copper and cadmium are potent inducers of MT in animal tissues [ 131. Although there is no clear evidence for the induction of MT by these metals in human tissues, the present findings on positive correlations between renal MT and cadmium, and hepatic MT and zinc support this view. Similarly, a close relationship between renal MT and tissue cadmium of smokers and non-smokers [5] and a positive correlation between MT and zinc in human liver [6,14] have been observed. These data indicate that MT in human kidney is mainly induced by cadmium whereas in liver it may be preferentially induced by zinc and possibly copper. However, since induction of MT has also been reported after various stresses [15,16], factors like the hormonal [17,18] and nutritional [19] status and even the type of death [20] might contribute as well. As shown in Fig. 4, there seems to be no correlation between hepatic and renal MT levels which we have also observed in a recent investigation with 145 postmortem samples of liver and kidneys [20]. Except in 2 individuals, MT levels in human kidney cortex exceeded those of the liver. However, in these cases hepatic Zn and renal Cd levels were more than twice and less than 50% of the average values, respectively. This supports the relevance for MT induction of the high Cd content of the kidney as compared to the liver, In contrast, MT levels of rat liver and kidney positively correlated with each other either after acute or subchronic exposure to cadmium and zinc or the acute administration to iodoacetate (unpublished observation). Therefore the chronic exposure of man to low levels of metals, in particular cadmium, and the preferential distribution of Cd-MT into the kidney may explain the observed lack of correlation. In conclusion, these results demonstrate that considerable amounts of MT are present in various human tissues. The particularly high levels of MT in human liver and kidney also in comparison to rats and the high levels of metals in these tissues suggest that the expression of MT in human tissues may respond to environmental factors, especially chronic low level exposure to metals. ACKNOWLEDGEMENTS
The authors wish to thank Dr. P. Schramel, GSF, Chemie, for the metal determinations and Mrs. M. Ederer ger for expert technical assistance. Part of this work was presented at the 4th International ment Analytical Chemistry in Medicine and Biology, F.R.G.
Institut fur ijkologische and Mr. J. LichtmannegWorkshop on Trace EleApril 1986, Neuherberg,
211
REFERENCES J.H.R.
Kagi and M. Nordberg
E.C. Foulkes
(Ed.),
R.J. Cousins,
5 K.H.
G.A.
influence
Drasch
and H.E.
of smoking,
(Ed.),
Hum.
and K.I. Yamamoto,
with iodoacetic
8 P. Schramel, Nachweis Anal.
Heilmaier,
Toxicol.,
acid and zinc, Arch.
A. Wolf,
biologischem
Material,
S.I. Tashiro,
by cadmium Schmidt
13 D.L.
and cadmium
1. Shimizu,
of metallothionein
and Biology in human
M. Furuta,
and metals
of
kidney
T. Yasutomi,
in malignant
38 (1986) 261-268. content and zinc status in various
Toxicol.,
and
tissues of rats
56 (1985) 247-251.
Die Leistungsfahigkeit
R. Seif and Presenius
and M.G. Cherian,
to metals.
expression,
Biochemistry
195-266.
der ICP-Emissionsspektroskopie
in biologisch-medizinischen
I. Effect
und
in Umweltproben,
and D.H.
Hamer,
Eaton,
N.H.
Anal.
zum
Fresenius
Z.
Stacey,
K.L.
Wong
indicator
von
tissues of rat in 22 (1981) 91-101.
in tissues by radioimmunoassay
and
154 (1986) 213-223.
and an effect of rus on human
metallothionein
gene
83 (1986) 3346-3350.
and C.D.
glutathione,
Klaassen,
Dose-response
heme oxygenase
Pharmacol., 55 (1980) 393-402. 14 J. Chung, N.O. Nartey and M.G. Cherian, - A potential
in various
salts, Toxicology,
of metallothionein
Sci. U.S.A.,
ions on rat liver metallothionein,
of metallothionein
of cadmium
Biochem.,
zur Druckveraschung
302 (1980) 62-64.
synthesis
injection
Cell specificity
Acad.
Eine neue Apparatur
Chem.,
Determination
method,
Natl.
Klose,
The induced
saturation Proc.
B.J.
Z. Anal.
of repeated
11 C.V. Nolan and Z.A. Shaikh, 12 C.J.
1982. Metab.
310 (1982) 209-216.
9 P. Schramel,
response
The Chemistry,
Metallothionein
K. Tanaka,
B.J. Klose and S. Hasse,
10 S. Onosaka
J. Inherit.
5 (1986) 27-33.
Concentrations
von Spurenelementen
Chem.,
New York,
and zinc metabolism,
1979, pp.
non-malignant tissues in human liver, Toxicology, 7 H.E. Heilmaier and K.H. Summer, Metallothionein treated
Base& 1979.
ElsevierINorth-Holland,
to copper
New York,
K.S. Min, C. Fukuhara,
K. Kobashi
related
in M. Webb
Elsevier/North-Holland,
6 S. Onosaka,
Birkhauser,
1) (1983) 15-21.
Summer,
cortex:
- aspects
The metallothioneins,
Cadmium,
Metallothionein,
Roles of Metallothionein,
Metallothionein
Dis., 6 (Suppl. 4 M. Webb,
(Eds.),
Biological
Metallothionein
of environmental
exposure
effects
and cytochrome
of various
metal
P-450, Toxicol.
Appl.
levels in liver and kidney of Canadians
to cadmium,
Arch.
Environ.
Health,
41 (1986)
319-323. 15 S.H. Oh, J.T. Deagen, Its induction
by various
16 F.N. Kotsonis agents,
P.D.
and C.D. Klaassen,
Toxicology,
synergistic
action
Effect
Cousins,
Biological
function
of metallothionein.
V.
234 (1978) E282-E285.
in hepatic
metallothionein
in rats treated
with alkylating
E. Kretschmer,
and norepinephrine
Dietary
of rats,
on zinc thionein
levels and in-
247 (1984) E318-E322. regulation
and glucocorticoids,
Revis and T.R. Osborne, Drasch,
Weswig,
of epinephrine
Hormonal
of glucagon
tion in the liver and kidney 20 G.A.
Increase
in rat liver, Am. J. Physiol.,
18 K.R. Etzel and R.J. 19 N.W.
and P.H.
Am. J. Physiol.,
51 (1979) 19-27.
17 F.O. Brady and B. Helvig, duction
Whanger
stresses,
protein
Environ.
P. Neidlinger
of liver metallothionein Proc.
effects Health
and K.H.
zinc: independent
Sot. Exp. Biol. Med., on cadmium
Perspect., Summer,
and metallothionein
54 (1984) 83-91. submitted
and
167 (1981) 233-236.
for publication.
accumula-