Document x5DGJwBMVgq9ame66VbNe0X2G
->zch. Tu:<: *.i. 1,3, IC-j -- i ; '! " . by Spriag'-r-Wrfsg t3J73
Interactions of Lead and Glutathione with Deiia-Aniinolin.-ulini'; Acid Dehydratase * **
2.-J. Ihpk* and E. Priced
Ins.
isy, ; Ta::i
Veterinary School of ilann-ovcr, .Germany
Deceived July 6.1973
Abstract. Because there were tendencies for normalization of lesd-5essUir
' parameters in ttniaub with low l.-.id burdens, these pl.c-ngmean "ere esnrnin.t-c!: .':
in tuYo and in 'vitro. Lend inhibited tbo enzyme 'k*!ta-*tr.-iao!.?ui:i:- acid uehyira-
taaefALA-D) dGse-dep.ea.ieatlr iai not rotnuecitively or irreversibly maineritively
to vitro. The lc4d-1.uock-*d portion of ALA-D 'ould be reactivated at ie,.-t r- irtiahy
by glutathione. Ti:,i3 part was higher in isd-C08T.intnated animals fhaa in the
Control group, tfcoasa there were no sitrnificaos tiiuerenees in the free
o: the
enzyme. The free part of the enzyme was normalized by a r'-.synthesis of the mole
cule. Therefore the dvjomCiution of the kv.d-blpeiced part and the part reactivated
by glutathione, seemed more suitable for determining the chronic lead burden than
tho measurement of a possible adapted total activity of ALA-l>i
Key wards': ALA-D -- Lead -- Glutathione -- Free and 'Blocked Part of .ALA-O,
Zosomrr.injjU^JV'J. 'Veil fieri in Tiervsr.sueh^n bei niedritrer IBYine! iscunc
Tendenzen zur Xormalisierung tier bisieaptlndijehrn i.'ar:~r`'r .as:. ".. trde
dieser ala Ad iStatian intvrpr-e'...-te Vorgtna in :> uad fa vL.-j m-nr-aft. 3:ei
hsromte fit riVa Jh 0 it.i-Am:::./ vVid"y...*:re-jjii\v irtitise fALA-'D-
i, bn nam
und uitht k .f.it atari' o L-ir :rrevm~'0y! ko'upe'itiv. Der durch 3.-i r .otk.ovte An tea
dor AI--V-D war -bet verm-hrt Ihnkar.t ualnh-rten I'-rsufhstietvn hiker cis bei
KontroUtiercn. Dag'-aen hestanih-n ini freien Auteii kei.ue ? umiakan ten Enter-
schiede zwisci.en den bviden Urunpen. Die JsTonnaMsWrttn!; ties fr-.-lea Ant-.-iis
erfolgts fiber cine I.eiisynthese ties Kr.z-.nns, donut erscheint die -Vectuag ties
durch B'.ei inaktivierten, riurch Gliitatkion reuktivierti-n Anteils d'i-rses F-.-rmectes
eher geeignet,, cine ehronisehe Blcieinvvirkun' fcswuatsHe?, cis die >f-.->ui:r der
moglicherweise wieder normalUierten ALA-D-Aktivitut.
ScktSssthtfrtfir: ALA-D von ALA-D.
Blei -- Glutaihion -- Frcier und bleckierter Tail
* Supported hy Psuieehe Fprscbnnzfgemeinschnft.
'* Partly p.res-niei1 at the 14, Spring ileethm r.f the Deutsche P.hoztnnk'rio-
? gis.che Geeriisrhsft, l.farrh Id to 21, 1973. in .Mainz. -
j
>1
*r
N27617
I9
154 H.-J. Hunk? and E, Prigm
The results of cur mvn -:q*ri^;.:sAs & sh-n ; r-'at yd 'A'*t :i tufT-r^a*
u>?es of '.ad via driakhtif ".ut$r Lau- the" Jiv- \i.i
c't.tttrts fcf
some parameters have tend to normalise after some weeks of lead ex
posure. In these experiments the excretion of d'.-ira-aminoit-vtilinic acid
in tiring decreased after an initial increase and na^i:-J the values of
ccrArc] animals after some weeks.(Trigge, .1971: Frigge and Hapke, 19.7.1;
Hapke, 1972). Bonsignore (iOol) made similar observations in rabbits,
in vhibh the excretion of velta-aminolevulinie nnid remained normal
though the lead application continued. Lelmert (197;1) interpreted this
as correction of a disturbed equilibrium.
In the same wav the activity of the delta-aminolevulinic acid de
hydratase (ALA-D) in the blood of the sheep increased after a short
period of inhibition in the beginning of t he lead application (Hapke, 1972t
Fassbender, 1973). The inhibition of the ALA-D explains i'he augmented
ex..re:ion of the delta-amir.v'.cvulinic -acid in -the urine. Only in a late
s: of the symptomless intoxication (i.e. more than 3 months} the
a., tivity of ALA-D remained low.
As these phenomena can be interpreted as a.n .adaptation to small
amounts-of lead, the enzyme ALA-D was invo t;rated in relation to its
inhibition bv lead .and to it-- react iv trior, l-y tHi ->!- ? like glutathione. The
part of ALA-D activity blvked by load, should be measured by the
reactivation exnerimeats.
Ulcfhods
The activity of ALA-D and of the reactivated par: o" ALA-D -was measured
by the method of Haas el cl. (li'72) with a few variations. fhe meiss-wmcnts were
r vrr.'-d out 1, for .determination of .normal values in '.Liferent spec;';*, 2. for th;
determination of the .enzyme after oral and intravenous application of lead nitrate
in rats and rabbits, and 3- for in vitro experiments after addition of Scad p.-vdo-
tathkme to the blood.
1. The normal values were determined in 7 healthy mjn, 9 horses, 25 doss of
d: "treat breeds. 20 beagle.-, 5 > cows, 16 piss, 13 rats and 4 rabbits, using fresh
L: wd with heparin,
2, 00 f-male Spra-nte-Dtv.i;y rats wore
f.;.- the determination of the
tr.r.rt'.e activity after oral at it ion ,f 'rad. The sc..' with a:i ,ivvr..:e wois'.t
f t g were divided into tit'-.- rvsps. Thy :;.r.-: srocp rv-.d as >. ,.ttmi .yrr-ip a:. :
r-' . .yd water. The second truer ri~-vivi w-d-y --:ti-1 l',t..',2I : ! ., :i r.ir, vt-i
iid
the third gmen r- -vyd water with
h. b-.i-l :::,.\i!v. Ti,-y v..-r-*
f t v-ith **Ssnuf I'crtigfut.ti.r '. The water and .f ed consumption was measured
cry and. based on the body - .h'.s. the daily dose of lead v. ,,s cn'rulated. Jb?
.-a: t received 14.7 and 27.5 c: hv.u per kg ar.d day. Out of each group 6 rats were
hi'.' 1 by d.-enpitation in deer- 'hlomform anesthesia after 1, 2 and 4 weeks and
5 months (13, 14 and 15 .-..sim.tls). The .activity n: the ALA-D tvts measured
in blood, the it-ad <vn'",nrr.itcna was incnsure-l i-t :ve bi rat, !iv-r, kidney, in
i and in the hair of
..do. "i'i.e ,'.-jter:.".ir,.:ti,:-. ;l,e ; 1 -,v.;s performrd
Airriiy measured by 77-. - rner. iiaum-ver.
t
ph-tam'-irtaaliy si sine .u.. ;:.:u.vA.-:l:--d. In f> iihring Vertigfutter) 1 | Irvatnter.c wr.d for 17 i i part of tire ALA-'D Vt
3. The activity of 21 cows in, vitro by a Ir. two .specimens of c the bic-ed incubated *-
To investigate the } of Liacweaver and B ) manner: To 4 of S ja: J sampii* 0.29 ml watt jf centra: ion c-f 0.4 ppn ( amounts of substrate acid solution, pH 6.-S f 1.0 ml. To interrupt ; copropo rpkyrinogen. 1 b (Lichtmnnn. and described above.
The activity c! : vitro by lead. Thor Art amount of lend &r-d pig 'blood bloc ;
The inhibition ; by the graphic me i uALA-D activity 1.; t: iivelr. As indict* ; phobilinogen prod of lower concen.tr: between the two r : by lead.
" The ALA-D it > glutathione (Fig. C > vas not complete ? :,y k-a-1, the loss . :-,rcv 1 :-r.vr-vn t}' -*? which is reactive | previously).
The determine ' blocked or.reactiv : normal lead expo s'-osittve ~reties, c Fxr-trtrrten's vvitk 'vmr-arr-: fA2.' :
DUP040007931
.-iuc - 'i cubages ot j weeks of load ox,.-r-:n ii:c-!vn:]i:i:e acid .reached t he values of . .; Priggo and liapke, 1071; ; .Jar observations in railbits, ,-uImic acid remained normal Lchnert (1971) interpreted this
e delta-aminolovutimc acid dej shefep increased after a short ?1ead application (rlapke, 1979: ALA-D explains the augmented id in the urine. Only in a late (i.e. more than 3 months) the
>,tcd as an adaptation to small 3 investigated in relation to its by thioles like glutathione. The d, should be measured by the
ated part of ALA-D was measured variations. The measurements -were lues in different .species, 2. for the ravenous application of lend nitrate easts after .a ddition of lead or glu-
"hrelibj- mem 9 horses, 25 dogs of 13 rets and 4 mbhiis, using fresh
sad for'the determination of the 'be animals vrith an average weight ; group served as control group and rater with 0.0321 % lead nitrate j 0.0!005 % lead nitrate. They were t feed consumption was measured y dose of lead was calculated. The day. Out of each group 6 rats ware -thesis after i, 2 and 4 weeks and .ivity ot the ALA-D was measured red in the blood, liver, kidney, in ' nination of the lead was performed .
p!.?t<.-m4'*.caTy
.; : ' .. r
. -.r. .
.. . ..
mutria method. In four jiuti- an-1
r.i'-I .t. with.\
> <4 2.5 kd fV.-.i:
Hoeing Ferti_Tut*.cr) 1 m-z lead, he body weight wa.viejevd hittaves.o-^ty.
treatment and for 17 d.tys tlicrcaher the activity of ALA-D and of the reactivated
part of the ALA-D w.-.-r nwif.ir-.'L
3. The activity of ALA-P vras measured in fresh 'blood of 10 docs. 9 pigs atai
21 cows in vitro by adding increasing doses of lead (0.1; 0,4; 0.7 and 1.0 ppm.
In twp specimens of cow blood 1.5 ml of a 0.1 31 glutathione solution was added to
the blood incubated with lead.
To investigate the mechanism, of inhibition of the ALA-D by lead, the. method
of Lincwcaver and Burk was used in 4 blood specimens of cows in the following
manner: To 4 of S samples with U,2 mi blood was added 0.55 ml water, to 4 other
samples 0,29 ml water and 0.10 ml lead solution ctf 1 pptr, that gives a lead con
centration of 0.4 ppm in blood. After an incubation time of 15 min increasing
amounts of substrate: 0.025; 0.1: .0,23 and 0.5 ml of a 0.02 31 delta-aminolevulinic
.acid solution, nit e.S, were added to the sample',. The substrate was filled uo to
1.0 ml. To Interrupt the next step, the transformation of porphobilinogen to
coproporphjTinogen, all specimens were incubated in a nitrogen atmosphere for
i h (Lichtmaan and Feldmann, 1903). The further procedures were the saree^a'3
described above.
Results
The activity of ALA-D was inhibited in. a dose-related manner in
vitro by lead. There were some species-differeneies, as indicated in Tig. 1.,
An amount oflcad which inhibits only 10 or 20 "o of the activity in dem
and pig blood blocks nearly 90% of the .activity in cattle blood.
The inhibition of the ALA-D activity by lead can be demonstrated
by the graphic method of Lineweaver and Burk. Thi3 inhibition of the
ALA-D activity by lead was not competitively or irreversibly compe
titively. As indicated in the Fig. 2, the maximal velocity of the por
phobilinogen production and the velocity of the reactionjn the presence
of lower concentrations of the substrate are reduced by.lead. The space
between the twb eurves is that amount of the enzyme, which is blocked
by lead,
f
The ALA-D inhibited by lead could be reactivated in vitro by
glutathione (Fig. 3). The reactivation of the blocked pad; of the enzyme
was not-complete by glutathione. The more the enzyme was inhibited
by lead, the less the activity could be increased by glutathione. The
space between the two curves in Fig. 3 represents that part of the enzyme,
which is reactivated by glutathione (or which was blocked by lead
previously).
The determination of the two parts of ALA-D, the free and the
blocked or reactivated part, in different animal species and in men with
normal lead exposure show, that only in men and cattle, the two lead-
sensitive species, could the ALA-D activity be reactivated by glutathione.
Experiments with penicillamine (2.5 to 40 mM in blood of cattle) and
dimercaprol (0.25 to 25 mM) did not produce uniform results. The
<1
/
T7 l
t
DUP040007932
> t *P
4
Fig. U Doss-depending inhibition of ALA-D by different concentrations of lead. in vitro in dogs, pigs, and cows
rig. 2. Eolations.between the reciproke vstasltie* of the enzyme-ALA-reaction and the reciprciks substrate concentration in b'.pjd of cattle, demonstrated in the -way
of Line-weaver and Burk
V, ALA - 0 activity
!
.!
!
<0.1 0.1 Oil 'gad in blood
<0.1 13.3
52.4 lead iri teai rs
<0.1 .3.3 43 4 lead in oonss
U 7 27 5 mg lead per leg and d ay
Fig. 4
Tig, 3. Dose relations between ALA-D activity and lead concentration (added to 'blood specimen of cows) or iead J>iu3 glutathione (0.1 M) concentration
Fig. 4. Free (lower port of the columns) and by dutathioAe reactivated (i.c, by lead blocked) form (double-lined rect-inghs) of ALA-D in the blood of rats, fed with d;~-:.-ent dose? of lead. The nmnbnrs in the cohnnr.s indicate the Did concentration
in blood. i,,.;r* sr.i bones of the .animals (ppm)
In
Table 1. ALA-D and re. , uMpcrp
ALA-D
xa
man cattle dos 1 dog 2
pig horse rat 1 rat2 rabbit
S24 234 240 12S 405 262 255 13C 1040 SSf
0.0-0.1 453 41 170 Si 2152
A group of 20 be dog 1 - bastards of did
6 young rats in th. rat 1 - adult rata
reactivation of the centration of these In horses no activ activity was measu was higher in. older
It is concluded ALA-D activity of by lend. This effec environment. The r s by a new synthesis
In rats which re ; parts of ALA-D v activity of ALA-D ; The small di/Feren :
in hair and hones was found in spite ; of lead during 5 u part of the ALAthan in control at ; demonstrable by < ; level and daratio: ; amount of the ler There were no di: weight and ths fc
DUP040007933
I i
1
2 4 20 Fir, 2
40
HiTcreat concentrations of Ic-ad i cows
,f the enawne-AIA-reaetjoa and cattle, demonstrated in the wav erk
jP
!!
t
if
il 1
i*
0.1 0.1 0.1 lead in blood
0.1 13.3
52.4 lead tn hairs
0.1
'3.3 .
48 4 lead in
bones
0 14.7 27.5 mg lead
par kg and day
Fig. 4
d lead concentration (added to one (0.1 M) concentration
ithiooe react: rat'd ti.e, by lead in the lAoi of n'ts, fed r.-irh Indicate the lead con rrttratioa nimah (ppnt)
.'Ciordct: i.o i.c ; ! ar.-i < A'..:.Aar
1 57
Table!. ALA-L and reactivated \LA-1) in diffrent :tM j-.rphoboitm lit;> ryd V'-- I ceils
* no- `-.voccied to`./.ad honr
ALA-D ii
71
r: vti rated
ALA-D zt
r.
ALA-D revet. AJLA-JL)
lnan cattle deg i , dog 2*
pig horse rat 1 rat 2 rabbit
024 254 244 2-5 w-5 2<:2 23-:. i:;o 1040 Cxi
A 0 ,, r..:
1..J 49 110 50 2152
7
13 23 20 15 9
5 4
1SI4 423 331 271
217 155 232 12.5
713 0,0^0 s
2!J 150 1302
53 15
7 9
19 20
3 <> 13 u 4
1.90 1.75
--
-- 1.34
--
"
A group of 20 beagle dors in the Mice age and the same body weigh:; dog 1 -- bastards of ditTsfent aces .end weights.
*.y02Bg rats in tbs age of $ .weeks, body weight between 129 end 139 g; rat 1 - adult rats.
reactivation, of the partly blocked ALA-D did not depend on the con centration of these two compounds in blood. For details see Table 1, In horses no activity of ALA-D could be determined- The highest activity was measured in rabbits, The reactivated part of the ALA-D was higher in older rats than in younger onc-3.
It is concluded that in naturally oecaring lead contaminations the ALA-D activity of sensitive species as men and cattle is partly blocked by lead. This effect- can be explained by the ubiquity of lead in the environment. The rest of ALA-D is brought up to the necessary activity by a new synthesis.
In rats which received lead for 5 months the free and the reactivated parts of ALA-D were measured at- the end of the experiment. The activity of ALA-D in ihe tear, anniiais was as high as in cont rols (Fig. 4i, The small differences were not .-igniueant. The conc-cntrr.:k>ns of lead in hair and bones were high in the lead-fed animals. In blood .no ie-i was found in spite of the contamination of the animals with high amounts of lead during d mo.'ths. The lead-blocked and glutathione reactivared part of the ALA-D activity increased in the lead-fed animals higher than in control animals. The action of lead in these animats was only demonstrable by determination of the reactivated part of ALA-D. The level and duration, of the contamination could be determined by the amount; of the lead in organs such as bones and hair (Sterner, 1972,'.
There were no differences between the groups with regard to the body weight and the 5,-od efficiencies. At the beginning of the development of
; I.
*&
7
t
DUP040007934
t53 K.-J. Hapke ami E- Prigge
M P20 / R3C r.
fig. 5. Activity of ALA-D (white columns) and of reactivated ALA-D (erprersed naiAIok-sporehrtbinno.rrene, produced p?.-iiterr.-d blood cells ani hour) in r.Vs. fed with two different doses of'lead for several times. After 7 days :<* whuie ALA-D activity is partly blocked by lead in a u-ase-reiau-d imunsr. Tibs b.ovbcd part increases during the experimen t and t he free part regenerates to the control values
chronic 1 ad intoxication a short reduction of the free part of ALAdP tvas seen in rats. The amount of this reduction was. that part, which could be reactivated by glutathione (Fig. 5, upper part of the columns) after the lead contamination of 1 week. Then the blocked part increased slowly and the free part showed the trend to normalization (Fig. 5, columns after 14 days). In control animals a part of ALA-D was also blocked as they got-older; however, these animals did not receive leadfree food. The lead content of the food was between O.i and O.D ppm dry substance.
To study denoco synthesis of the ALA-D, which was reduced pre viously by lead, lead was- injected intravenously into rabbit?. The injection of i mg lead-kg body -weight de:--ei?i the activity of ALA-D immediately (Fig. 6). The whole activity then increased (i.e. the sunj of free and reactivated activity) as a result of increased free c-nrvme. The observation, that the whole activity -eem;? to be lower than the free part, is due to the ni' thod: The development of the color of porpho bilinogen with .EhrlichV w.-ig-nt j< inhibited by ihhh fa riim free also
*
Fig. 6. bccrcase* of the of 1 nig lead p-.-.r kg toreactivation with sriat
' by Fig. 7. Scheme of th-.- k AUililflls. 1 phllSd *** in?:
Table 1 for other sj creased relatively q activity. Therefore, of ALA-D,-and not t
As indies:-?'! by' by lead can le rea method the degree sensitivity of AL.V-I by glutathione differ
After chronic le: increases -and the frr ILhed too, th-.t cue
DUP040007935
(
Fig. 1, Dose-dependiag inhibition of ALA-D by different concentrations of lead tn vfin? in dogs, pigs, and cows
Fig/& delations.between the reciprokevelocities of the enzyme-ALA-reaction and' , the reciprako substrate concentration in bloud of cattle, demonstrated in the way
of Lmeweaver and Burk
% ALA - D activi ty
Jig. 3
Fig. 4
and day
Fig. 3. Dose relations between ALA-D activity and lead concentration (added to blood specimen of cows) or lead plus glutathione (0.1 M) concentration
Fig. 4. Free (lower part of the columns) and by glutathione reactivated (i.e. by lead blocked) form (double-lined rectangles) of ALA-D in the blood of ra'ts, .fed with different doses of lead. The numbers in the columns.indicate the lead concentration
in blood, hairs and bones of the animals (ppm)
*
In
Table!. ALA-D and re. u Al porp
tel-n
X0
man cattle dog 1 dog 2*
P`S horse rati rat2*
rabbit
924 234 240, 12S 40o' 262 23$ ise 1040 38
0.0- 0.1 159 4( 170 5( 2132
A group of 20 be dog 1 -- bastards of diff
a young rats in th< rat 1 - adult rata.
pr;-1 " reactivation of the ; cenfcration of these In horses no activ activity was meastr was higher in older It is concluded
* ALA-D activity of: by lead. This effec environment. The n by a new synthesis. In rats which re parts of ALA-D v activity of ALA-D The small different in hair and bones
... was found in spite c of lead during 5 m part of the ALA-i than in control an demonstrable by d
level and duratior amount of the lea There were no difi weight and the fee
DUP040007936
Ii:tonictiun.-i of Lead and Ciurathione
153
1 ALA-0 activity
,)d 150 b
` reactivated ALA-D (expressed slood ceils and hour) in rat3, fed After 7 days the whale ALA-D led manner. This blcft'kpd -part egeneratea to the control values
of the free part of ALA-D ctioQ was that part, which upper part of the columns) t the blocked part increased 1 to normalization (Fig. 5, a part of ALA-D was also imals did not receive leadctween Q.i and 0.3 ppm dry
D, which was reduced preeftoBslj* into rabbits. The ssed the activity of .ALA-D ten. increased (i.e. the sum ; of increased free enzyme. 03 to be lower than the free at of the color of oc-.rpho"SJ thiols :'.a vitro Idea also
l.phaS5 2.pr>elS.9 (adaptation)
Fig. 7
Fig- 6- Decreases of the ALA-D activity in the blood of 4 rabbits after i.v. injection of 1 mg lead per kg body weight. Free ALA-D (lower iine) and whole ALA-D after reactivation with glutathione. The curves show that the normalization is caused
by an increase of the free part of ALA-D Fig. 7. Scheme of the lead action on ALA-D activity in normal and in lead exposed animals, t phase - increase of the blocked part of ALA-D; 2 phase increase of
the free part of ALA-D to normal values
Table i for other species). The activity of the free part of ALA-D in creased relatively quickly, in parallel -.vith the increase of the whole : activity. Therefore, we interpret the increase as due to. new synthesis ] of ALA-D and no t to a slow liberation of lead.
j Discussion | As indicated by the results, the part of the AIA-D which is blocked ! by lead can be reactivated by the addition of glutathione. By this : method the degree of the lead contamination can. be determined- The
sensitivity of ALA-D to lead and the reactivation of the blocked enzyme | by glutathione differ between species, | After chronic lead contamination, the reactivated part- of ALA-D' | increases and the free part tends to normalize. Haas ct at. (1072) estab! lishe.d too, that the part, of ALA-D reactivated by glutathione increases
DUP040007937
160 H,-J, Hapke and E. Brizge
with increasin' lead concentrations of the blood in niyn. In sensitive species like men and cattle a pin of AI.A-JP is blocked by the lead In the normal environment. Tin* remainin'-; part of ALA-D is supplemented by a new syntheses of Tin cnsymei
We conclude that established, adaptation to small lead amounts may be explained by the following .scheme (Fig. 7): In the normal environ ment a part of ALA-D is blocked even in individuals who are not leadintoxicated. With increasing lead concentration in the environment, the blocked part of ALA-D increases first. By a regulation mechanism the organism is able to supplement the lost part.
The results indicate that, due to the unavoidable lead contamination of the environment, the enzyme patterns of all organisms are under the influence of lead. Therefore the question of a non-toxic level of lead cannot be answered. The state before the lead contamination begins strongly affects the action of lead at higher doses. Hernberg et cl. (1970 a, b) considered that a non-toxic level could not be determined for lead.
Short lasting and. abrupt increases of lead intake cause an inhibition of the free ALA-D activity, blow changes of the lead intakes can be partly compensated by the healthy organism. This phenomenon is interpreted as adaptation.
The most sensitive parameter for determining lead action on organ isms has been shown by these investigations and of those of ILtus et cl. (1972) to be the measurement of the reactivated part of ALA-D, With this test, the action of k-ad can. be determined, even, if the other para meters such as increased excretion of delta-aminol.^-ulinie achl in urine or decrease of the ALA-D activity on blood tend to normalize.
References
Bcnsignore, D.: Biochemical approach to the physiopathology o? porphyrin metab olism in lead poisonine. Lav. umano 13, Ol'O--017 .(1961)
Fassbendcr, C. P.: Versuche acr Eazjmdi.icnostik der subklinLchen B'eivergiftang be-i Schafeii. Inaug.-Diss., Hannover 1973
Haas, T-, Macho, W., Schaiicf, K.-IL, Macho, K., Klavis, G,, Stumpf. R.: Zar Beatisunung der Delta-Amino'avalinsaure-Dchydratase und ihrer diagno.viichen Wertiekcit. Int. Arch. Arhei-.o.-ied, 30, $7--164 (1972)
If.spke, Il.-J.: Subkiiaische Keivergiitims bei -Sehafen. International Symposiam "Health Asoects of Ettv-ircarr.en'tai i'oiiution n-jth Lc k T*.. Ai.asror'Iam. 1972
Hemberg, S., Xlkkinafl, J-; Kr.-vrc - ir.i.AAon by lead under normal urban conditions. Lancet 1970 1. 63 (15/76a)
Herrtherg. S.. XiUcanen, J., Tela,Vaikcaen, S., Xordraan, C- H.: Erythrocyte ALA-deayJrasasfc as at test of lead exposure. Int. Conf. Chens. Poll. Hum. Ecol., Prjgue 1970 b
Lehnert, H.: Biokybernetische Probh-m.e der Hlcibelastung. I'.eferat 'VDT-KoteeLssioa Keir.haltung der Luft, 19. April 1971, Dusseldorf (1971)
-i I
Lich'.r.'anti. H. C., TV poisoning and iro.
Prirge, E.: Vert ache's Hartnov . i9T'
Prig;:A V.. v -.jvt.*, 1
.Bieiyercilmnu be
Sterner, V.',: Lie ha's gen "seignete ifet lut'd Tier, Arch. L
s
DUP040007938
, mon. i.u ivasitivo , p.-ked by the bid in
JUA-JO i' supplemented
f to small lead amounts may
.. 7): In the r.grm.d environrulividuals who are not lead.tion in the environment, the % rvgttl.nh,u ir.urb.uvi'tn the
ivoidahh- lead contamination
f all organism?, arc- under the of a non-toxic level of lead e lead contamination begins dter doses. Eernherg et at. 1 could not he determined for
ad intake cause an inhibition s of the lead intakes can be anisin. This phenomenon is
mining lead action on organas and of those of Haas cl nl, 'rrated part of ALA-D.^VVith nod, even if the other paraa-aminolevulinic acid in urine i tend to normalize. 't ; -* ->
Sioparholosy of -porshrrm meiab-017 (156tj i der subkiisischea Bleirergiftang
, Klavis, G., Stuxapf. ft.: ZurBi-iratase und ihrer diaenostisehea >1 (1972) chafen, International Symposium vith head", Amsterdam 1972 n by lead und:r normal urban
S., .Jfordsua, C. H.: 'Errdtfocvte !at. Conf. CLr-m. Pell. Hem. Eco!.,
"e5beh<tfur.r. BeArr: VrH-Kom.. ioisseidor: vtVTt)
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Interactions of Lead and Glutathione
101
Lich'taaaa, U. C., !V!i:r.:urn. F.: In vitra pyrrole nr.-li porphyria synthesis in lead polsonine cud iron dwtoemey. .1. efin, invest, 12, 1190")
?ri?i5e,U.sYersuehe*ur lrTultdi.tgnP4C der IHeivergiftong bci Schafea, Iaaug.-jplss., Hannover 1971
Sterner, IV.? Die m.iru!aly* -- bioyiidf-rs fur epidcmiolpciM'he Vr.tc?sttehunge.'i gceipietcMtthodes.uri-'eststeUu.ig votiocliwennf-raiibeiastangea oeiifcnsch and Tier. Arch. LeSen.-mkt.-llyg. 10,209--21U (1972)
Prof. Dr. 1L-.T. Hapke i.-utiuit Idf ]'; ir:rt.-i 1tpI-v: =j Abtcilung fur Tosikoioe:.* Tiorarutlkhe Hochschu-e B-3G0O Hannover Bischofshoier Dim 15 Federal Republic of Germany
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