Reviews of Physiology, Biochemistry and Pharmacology, Volume 125

199 Pages·1994·3.493 MB·English

by  K. W. Bock (auth.)

Reviews of
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Editors
M.P. Blaustein, Baltimore • H. Grunicke, Innsbruck
E. Habermann, Giegen • D. Pette, Konstanz
H. Reuter, Bern • B. Sakmann, Heidelberg
M. Schweiger, Berlin ° E.R. Weibel, Bern
E.M. Wright, Los Angeles
With 62 Figures and 41 Tables
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Contents
Aryl Hydrocarbon or Dioxin Receptor:
Biologic and Toxic Responses
By K.W. BocK, Tfibingen, Germany
With 5 Figures and 8 Tables ................ 1
Physiological and Metabolic Responses to
Hypoxia in Invertebrates
By M.K. ,REBAHSFIRG I. ,CIWEDRAH U. ,REZTUERK
and H.-O. ,RENTROP Dfisseldorf, Germany
With 20 Figures and 6 Tables .............. 43
Calcium as Modulator of Phototransduction
in Vertebrate Photoreceptor Cells
By K.-W. KocH, Jfilich, Germany
With 1 Figure ....................... 149
Subject Index .......................... 391
Indexed in Current Contents
Rev. Physiol. Biochem. Pharmacol., Vol. 521
© Springer-Verlag 1993
Aryl Hydrocarbon ro Dioxin :rotpeceR
Biologic dna Toxic Responses
K. W. BocK
Contents
1 Introduction ..................................... 2
2 Levels of Persistent Receptor Agonists (PCDD/PCDF) in Humans ..... 4
1.2 Toxic or TCDD Equivalency Concept .................. 4
2.2 Pharmacokinetic Implications ....................... 6
3.2 Basal PCDD/PCDF Levels ........................ 7
2.4 Levels of PCDD/PCDF in Exposed Populations ........... 7
3 Ah Receptor ...................................... 9
1.3 Allelic Variants of the Ah Receptor (Ahb/Ah d Polymorphism) .... 9
2.3 Biochemistry ................................. 01
3.3 Mechanism ofA h Receptor Activation, CYPIA1 as Example .... 11
4 Biological Responses ................................. 31
1.4 Transcriptional Activation of Genes Coding
for Drug-Metabolizing Enzymes ..................... 31
4.1.1 AhR Gene Battery ............................. 31
4.1.2 Cytochrome P4501A1 (CYP1AI) ..................... 51
4.1.3 Cytochrome P4501A2 (CYP1A2) ..................... 61
4.1.4 Cytochrome P4501B1 (Clone )1 ..................... 71
4.t.5 NAD(P)H: Quinone Oxidoreductase (NQO0 ............. 71
4.1.6 Aldehyde Dehydrogenase (A1DH-3c) .................. 81
4,1.7 UDP-Glucuronosyltransferase (UGT1A1) ............... 81
4.1.8 Glutathion S-transferase Ya ........................ 20
4.2 Transcriptional Activation of Genes Related
to Growth/Differentiation ......................... 20
4.3 Interaction of the AhR with Other Transcription Factors
(Members of the Steroid hormone Receptor
Superfamily, c-JUN and c-FOS) ..................... 12
4.4 Interaction of the AhR with Cell Surface Receptors .......... 12
5 Toxic Responses ................................... 22
1.5 Wasting Syndrome ............................. 22
5.2 Immunosuppression ............................. 23
3.5 Teratogenicity ................................ 52
5,4 Chloracne ................................... 26
5.5 Carcinogenicity/Tumor Promotion .................... 28
Institute of Toxicology, University of Tfibingen, Wilhelmstral3e ,65 72074 Tiibingen,
Germany
2 K.W. Bock
6 Tissue and Species Specificity of the AhR Responses .............. 30
7 Potential Threat of PCDD/PCDF to Human Health .............. 30
8 Summary and Conclusions ............................. 30
References ......................................... 32
1 Introduction
Recent identification of the Ah receptor as a Iigand-activated HLH (helix-
loop-helix) transcription factor and the world-wide persistence of potent
receptor agonists such as 'dioxins' in the human body has renewed
interest in this receptor and its responses. Classification of the responses
as "biologic" or "toxic" must remain arbitrary. For example, Ah receptor-
controlled enzyme induction and its interaction with other transcription
factors and cell surface receptors can be viewed either as adaptive
responses or may be responsible for deleterious effects leading to
pathologic conditions and diseases.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the extensively stud-
ied prototype of the dioxins and dioxin-like environmental pollutants
that include coplanar polychlorinatedd ibenzodioxins (PCDD), dibenzo-
furans (PCDF), and biphenyls (PCB) (Fig. .)1 Because of their potency
and widespread persistence in the environment and in animal and human
tissues, they have attracted both academic and sociopolitical interest. In
particular, TCDD has gained notoriety as a contaminant of the herbicide
Agent Orange and because of its release into the environment during
industrial accidents and the improper disposal of chemical wastes.
Studies in various animal models, in human and animal cells, as well as
epidemiologic studies of accidentally exposed human populations indi-
cate that PCDD/PCDF are responsible for species-specific toxic syn-
dromes including wasting, immunosuppression, teratogenesis, hyper-
keratosis, and chloracne, as well as cancer. Chloracne is a response
commonly observed in highly exposed humans.
Although differing by orders of magnitude in potency, most biologic
and toxic effects of PCDD/PCDF are believed to share a common
mechanism of action, as suggested in the classic review by Poland and
Knutson (1982). This mechanism involves their binding to an intracellu-
lar protein, the aryl hydrocarbon (Ah) or dioxin receptor, followed by
translocation of the transformed ligand-receptor complex into the nu-
cleus and its DNA binding to specific dioxin-responsive elements (DRE)
(Whitlock 1990) or xenobiotic-responsive elements (XRE) (Fujisawa-
Sehara et al. 1987) in the vicinity of tissue-specific subsets of genes which
Ah Receptor
Fig. .1 Ah receptor ligands 21 1
Ct',[~°"~TC' e ~ 3
CI ,.,~o.,,~,,. CI e',~,~/~,~ 4
7 6 5
DDCT Benzo(pay)r ene
7 -~J~OJ"~ '3 CH
CI e 4 Cl
PCDD 3-Methylcholanthrene
CI Cl .,~
PCDF 7,8-Dehydrorutaecarpine
H
'3 '2 2 3 ~ . N , ~
CI- "e'-r"5 if'-5 "Ct
H
BCP Indolo [3,2-b]carbazole
are transcriptionally activated ("Ah receptor gene battery") (Nebert et al.
.)1991
In this way the Ah receptor functions as a ligand-activated trans-
cription factor. In many respects, the mechanism of action of TCDD
resembles that of steroid hormones. However, the amino acid sequence of
the Ah receptor indicated that it is not a member of the steroid hormone
receptor superfamily but of HLH transcription factors related to develop-
mental genes of Drosophila (Burbach et al. 1992; Ema et al. 1992).
The risk that dioxin poses to humans remains uncertain. Many
aspects of the exploding literature on the dioxin receptor and dioxin
toxicity have been dealt with in recent reviews and conference reports
(Safe 1986; Skene et al. 1989; Whitlock 1990; Landers and Bunce 1991;
Banbury Report 35 1991). The present overview updates current know-
ledge about selected Ah receptor-mediated biologic actions, such as
enzyme induction, and about a variety of toxic effects such as carcino-
genicity/tumor promotion. Findings in experimental animals and hum-
ans are described and compared to mechanistic studies in cell culture
models. Extrapolation from animal models to human health risk and
4 K.W. Bock
gaps in our knowledge are emphasized, the most challenging problems
being the tissue and specificity species Ah of receptor-mediated responses.
2 Levels of Persistent Receptor Agonists (PCDD/PCDF) ni Humans
2.1 Toxic or TCDD Equivalency Concept
The compounds: PCDD/PCDF are present as complex mixtures in the
environment and in animal and human Since tissues. tmhiexsteu res exert
most of their biologic and toxic effects through interaction with the Ah
receptor, many national agencies tried to assess risks associated with
exposure to PCDD/PCDF mixtures by relating the potencies of indi-
vidual congeners to that of TCDD, the most potent compound. To
facilitate risk communication internationally, a working group of the
North Atlantic Treaty Organization's Committee on the Challenges of
Modern Society developed an updated schemdee scribing international
toxic equivalency factors (I-TEF) (Nato/CCMS 1988; Kutz et .la .)0991
I-TEF values have been adopted by the United States Environmental
Protection (EPA) Agency and by many other national (Table agencies .)1
For chemicals to be included in the I-TEF concept, the following
criteria should be met: )a( they should bind to the Ah receptor; )b( they
Table .1 PCDD/PCDF levels in the general population 1980-1991
Congener Germany USA" I-TEF a
Blood" Blood b Milk b Blood
n( = )201 n( = t00)
2378-TCDD 6.3 2.2 1,2 5,2 0.1
12378-PeCDD 8.31 9.5 9,5 21,0 0.5
Total HxCDD 1.67 3.13 3.93 0.211 1.0
1234678-HpCDD 92.4 1.14 39,6 781 10.0
OCDD 610.3 228.6 8.891 4711 100.0
2378-TCDF 3.2 t.8 0,1 1.3 1,0
Total PeCDF 39.0 9.7 3,31 8,51 0.5
Total HxCDF 7,43 1.91 3.61 7~33 0.t
Total HpCDF 24.9 4.51 7.5 4,2 10.0
OCDF 4.2 < 4.4 0.5
Total PCDD/PCDF 43 61 81 42
(I-TE)
All data are given as parts per trillion (ng/kg lipid)
a Data from Schecter 1991, except b
b The comparative data for blood and milk are from one woman; from Wuthe et al, 1992
hA rotpeceR 5
should elicit dioxin-specific biologic and toxic responses; and )c( they
should be persistent and accumulate in the food chain. Several diverse
classes of compounds (in addition to PCDD/PCDF) bind competitively
to the Ah receptor. They include polycyclic aromatic hydrocarbons and
heterocyclic plant constituents (Fig. .)1 However, most of these chemicals
do not meet the last two criteria, namely, they do not elicit dioxin-like
toxicities and do not persist in tissues due to rapid metabolism. Therefore
these chemicals need not be considered for inclusion in the TEF concept
(Ahlborg et al. 1992).
Of the 75 positional isomers of PCDD and 531 isomers of PCDF
usually only the 2,3,7,8-substituted congeners persist in biota. Relative
potencies of PCDD/PCDF as Ah receptor agonists are comparable for
most receptor-mediated responses. Safe (1986) has summarized the
relative potencies of the environmentally relevant 2,3,7,8-substituted
PCDD/PCDF mixtures compared to 2,3,7,8-TCDD. A similar correla-
tion between toxic response potencies and Ah receptor-binding affinities
has been observed for non-ortho- and mono-ortho-substituted PCBs
such as 3,4,3',4'-tetrachtorobiphenyl (Fig. .)1 It is considered that these
PCB congeners may also be included in the TEF approach (Ahlborg et
al. 1994).
A data hierarchy has been established to assign the I-TEF values. In
general, priority was given to a result from long-term, whole animal
studies such as carcinogenicity. Since only a few data are available, data
of acute and subchronic toxicity were also included and in some cases
short-term in vivo and in vitro enzyme induction data. The utility of the
in vitro inductiond ata has been demonstrated. A reasonable correlation
has been observed between the binding affinity of PCDD/PCDF, induc-
tion of CYP 1 1A protein, and associated enzyme activities (aryl hydrocar-
bon hydroxylase, AHH, and ethoxyresorufin O-deethylase, EROD) and
toxicity data (Safe 1986).
Although antagonistic and overadditive effects have been observed,
interaction of PCDD/PCDF appears to be mostly additive (Safe 1986).
Furthermore, in rat and human cells cultures the potency to induce
CYP1A1 activity was studied using complex but defined mixtures
containing 49 PCDD congeners. The potency of each mixture could be
adequately described by adding the TEFs of the seven 2,3,7,8-substituted
congeners (Schrenk et al. 1991b; Lipp et al. 1992). The same mixtures
were investigated in an initiation/promotionm odel of hepatocarcinoge-
nesis (Schrenk et al. 1994). The results suggest that the TEF concept can
be used as a rough estimate but may overestimate the risk for the higher
chlorinated PCDD/PCDF.
The TEF approach can be used for PCDD/PCDF mixtures to
transform analytical results into toxic equivalents: E ([congener] × TEF)
6 .W.K Bock
= TE. This simple relationship is only valid when the individual congen-
ers exhibit an additive response. Although useful for risk management,
the approach has to be regarded as an interim procedure and needs to be
updated periodically as more toxicity data are generated.
2.2 Pharmacokinetic Implications
Both TCDD and higher chlorinated PCDD/PCDF persist in animal and
human tissues. These pharmacokinetic properties have to be considered
in risk assessment of these compounds. In the rat an elimination half-life
for TCDD of 20-30 days has been found (Piper et al. 1973; Rose et al.
1976). In humans, the half-life of TCDD is about 100 times longer, 6-10
years (Poiger and Schlatter 1986; Pirkle et al. 1989). For the higher
chlorinated PCDD/PCDF half-lives between 15-50 years have been
estimated (Table .)2 In these estimates calculation of half-lives have been
based on steady-state concentrations in human fat and on the average
daily intake of PCDD/PCDF, estimated from the concentration in
animal fat (Beck et al. 1989a). Animal fat constitutes the main source of
PCDD/PCDF for humans.in the diet. Important species differences are
also found regarding organ distribution. In rats, approximately 60% of
TCDD and >90% of the other PCDD/PCDF are stored in the liver,
whereas in humans 90% of PCDD/PCDF are located in the adipose
tissue (Schlatter 1991).
Table2. PCDD/PCDFIevelsin human taf calculated and sevil-flah Schlatter (from )1991
Fat concentration tl/2
)tpp( )sraey(
Congener "namuh lamina b
DDCT-8732 5.3 2.0 (determined) c 6
FDCT-8732 5.2 7.0 3.1 )detaluclac(
DDCeP-87321 01 7.0 5 )detaluclac(
FDCeP-87432 52 4.1 3.6 )detaluclac(
DDCxH-874321 01 3.0 51 a )detaluclac(
DDCpH-8764321 05 2 52 a )detaluclac(
OCDD 533 01 05 d )detaluclac(
ppt, parts per trillion
"WHO .)9891(
Beck bFrom et .la .)9891(
morFC Poiger and Schlatter .)6891(
seulaVd absorption rates. decreasing for corrected
Ah Receptor 7
2.3 Basal PCDD]PCDF Levels
In principle, PCDD/PCDF can be generated by the combustion of
organic material in the presence of sodium chloride and metal catalysts
such as copper, the latter leading to the production of chlorine gas
(Hagenmaier et al. 1987). There is evidence of world-wide distribution of
PCDD/PCDF in the environment and in animal and human tissues
(Schecter 1991). Relatively higher levels are characteristic of human
tissues from industrial countries and lower levels from developing
nations. Human tissue at present contains higher levels of dioxins than
ancient tissue. Still-born human infants, never having nursed, also had
very low levels of dioxins (Schecter 1991). Levels of PCDD/PCDF in the
general population of Germany and the United States are shown in Table
.1 Congener patterns and TEs are very similar in the two countries.
Comparable levels are usually found in serum, milk, and fat tissue when
the analytical data are based on lipid, suggesting the existence of steady-
state conditions. The main source (over 90%) of PCDD/PCDF intake is
food consumption (animal fat), leading to an average daily intake of 1 to
3 pg TE/kg in the German population (Beck et al. 1989a). Despite high
concentrations in human milk (Beck et at. 1989b) no accumulation of
PCDD/PCDF in different organs from infants were found, probably due
to the rapid increase of fat tissue at this infant age (Beck et al. 1990).
Dioxins have also been found in cigarette smoke (Muto and Takizawa
.)9891
2.4 Levels of PCDD[PCDF ni Exposed snoitalupoP
Several human populations had documented a higher intake of
PCDD/PCDF followed by illness. Tissue levels of PCDD/PCDF of these
populations may be important for epidemiologic studies trying to link
exposure to health effects (see Sect. .)5 For example, in the BASF
ehcsidaB( Anilin- dnu Soda-Fabrik) incident 1953, several workers were
exposed to TCDD-contaminated vapors due to an exothermic reaction
in an autoclave during a trichtorophenol manufacturing process. All six
workers studied developed chloracne. All were found to have elevated
TCDD adipose tissue levels even 32 years after exposure (Table .)3 On the
other hand, levels of the higher chlorinated PCDD/PCDF were in the
ranges found in the general population.
Two other examples document the worldwide distribution of
PCDD/PCDF in humans (Table .)4 First, studies in Japanese people
revealesdi milar PCDD/PCDF levels to thosef ound in Germany and the