[Dioxin-l] follow-up TCDD cancer potency/TDI history

[Tony Tweedale]

From: "Henshel, Diane S." <dhenshel@indiana.edu> Re:
>>This paper also shows that PAHs, tho binding to Ah,
>>  do not induce enzymes and proteins/do not get carried into the nucleus;

>PAHS (once bound to the Ah receptor) most certainly do translocate to the
>nucleus and induce enzymes, albeit not with the same potency as TCDD.  There
>is plenty of both enzyme induction data and mRNA increase data to support
>this, in multiple species and in studies conducted by more scientists now
>then I could list off the top of my head, well above a dozen or so.
>Benzo-a-pyrene (a PAH) is commonly used as one of the standards against
>which other EROD (a marker of P4501A enzyme activity) inducing-activity is
>compared.
----

I in-accurately summarized the '80 Poland & Glover paper 'A Model for the
Mechanism of Action of 2,3,7,8-TCDD'.  On p. 338 they say:

"We do not understand why nonhalogenated agonists for the receptor, eg PAHs
and b-napthaflavone do not do not produce the characteristic spectrum of
toxic responses produced by TCDD and its congeners. ...The ... [may] ...
binds differently to the nuclear  sites ... Alternately ... sustained
occupation of the receptor and the long biological half-lives of the
halogenated aromatic compounds ... In support of this latter possibility we
have found that MC [a PAH] and b-napthaflavone will produce thymic
involution, a response characteristic o TCDD toxicity."

Sorry about the mistatement.  Another cause was the author's distinction of
"true induction, i.e. de novo protein synthesis.", tho even there (p. 335)
they name several hepatic enzymes that both  MC and TCDD induce.  This
paper is pretty amazing--this and much more that was known about the
mechanism of toxicity, by 1980!

Tony Tweedale

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