[Dioxin-l] molecular mechanism of dioxin action

[Jon Campbell]

Hi, folks,

     Below is a short paper posted by dioxin researchers at UC Davis. I
found a link on Louise Oram's university web page, which guided me to the
article at http://dioxins-r-us.ucdavis.edu/Dioxin.HTML Thanks so much to
Louise for guiding us in this endeavor, even though she and Dr. David Bell
(who were apparently colleagues in the UK) did so quite inadvertently. This
short paper makes clear the molecular nature of the Ah Receptor site.

    Note that as I had originally hypothesized, a single molecule of TCDD
can bind to the Ah receptor and the bound complex is then transmitted to
nuclear DNA where it begins to disrupt the normal functioning of the cell.
My original sources of the hypothesis were popularized versions of the
analysis below.

Regards
Jon Campbell

MOLECULAR MECHANISM OF DIOXIN ACTION

Halogenated aromatic hydrocarbons (HAHs), such as polychlorinated
dibenzo-p-dioxins, biphenyls, dibenzofurans, and related compounds represent
a diverse group of persistent, widespread environmental contaminants.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin), the most
biologically-active and toxic member of this class of compounds produces a
wide variety of species- and tissue-specific effects (1,2) including: tumor
promotion, immuno- hepato- and dermal toxicity, lethality, birth defects,
endocrine disruption and induction of numerous enzymes, most notably that of
microsomal cytochrome P4501A1 and its associated monooxygenase activity,
aryl hydrocarbon hydroxylase (AHH) (1,2). The P4501A1 isozyme contributes to
the metabolic activation and detoxification of polycyclic aromatic
hydrocarbons, many of which are carcinogens (3). 

The induction of hepatic AHH activity is perhaps the best studied of the
biochemical effects resulting from exposure to TCDD and related HAHs (4,5).
Early experiments examining the induction of AHH activity by a series of
halogenated dibenzo-p-dioxin and dibenzofuran congeners resulted in the
identification of a specific receptor which bound these compounds saturably
and with high affinity. Qualitative structure-activity relationship studies
revealed that the ability of a compound to bind to this receptor was well
correlated not only with its ability to induce AHH activity (1,2,6) but also
its ability to induce toxic effects, such as thymic involution, wasting and
epidermal keratinization (1,2,6,7), suggesting that the receptor also
mediates the toxicity of these compounds. This TCDD receptor has been
identified and characterized in a wide variety of species and tissues (8,9)
and has been designated as the aromatic hydrocarbon receptor (AhR). 

Induction of hepatic P450IA1-dependent AHH activity has been utilized as a
model system to examine the molecular mechanism of action of HAHs. The
current model for the AhR-dependent P4501A1 induction mechanism (above) is
in several ways similar to that described for some steroid hormone receptors
and steroid-responsive genes (10,11). The unliganded AhR complex exists in
the cytosol complexed with at least three additional proteins (12).
Following high affinity ligand (TCDD) binding, the TCDD:AhR complex
undergoes a poorly defined process of transformation, during which hsp90 (a
heat shock protein of 90 kDa) and other proteins appear to dissociate from
the TCDD:AhR complex, the AhR complex acquires the ability to bind to DNA
with high affinity and transformed TCDD:AhR complexes subsequently
accumulate within the nucleus (12-16). High affinity DNA binding of the AhR
complex appears to require its association with at least one additional
protein, the Ah receptor nuclear translocator (ARNT) protein (17-20). The
binding of these transformed heteromeric TCDD:AhR complexes to specific DNA
sequences (Dioxin Responsive Elements (DREs)) adjacent to the cytochrome
P4501A1 (CYP1A1) gene leads to DNA bending, chromatin disruption, increased
promoter accessibility and increased rates of transcription initiation of
the CYP1A1 gene with the subsequent accumulation of cytochrome
P450IA1-specific mRNA (4,21-27). The presence of the AhR complex in a wide
variety of species and tissues and with its ability to act as a
ligand-dependent transactivator of gene expression suggests that many of the
toxic and biological effects of HAHs result from differential alteration of
gene expression in susceptible cells. 


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