[Dioxin-l] References about threshold

[Tony Tweedale]

"Henshel, Diane S." <dhenshel@indiana.edu> helpfully wrote me:
---

> To quickly address two issues only:
>1) Kd - for all binding (receptor ligand or substrate-enzyme) there is a
>characteristic rate of both association (binding to) and dissociation
>(unbinding from).  Some ligands bind quickly, and dissociate quickly
>(acetylcholine to its receptor) some bind quickly and dissociate slowly or
>not at all (bungarotoxin to the acetylcholine receptor) some bind more
>slowly and dissociate quickly (no quick off the top examples, I'd have to go
>to texts or literature now and I'm not in my office) some bind slowly and
>dissociate slowly.  A general rule of thumb is that the second message
>(channel opening, enzyme activation, whatever)is being generated through out
>the time that the receptor is bound to a stimulating ligand (aka agonist).
>Antagonists (competitive) bind but don't activate the second message
>(actually that's what bungarotoxin is).  PArtial agonists bind, sometimes
>not as well (ie slowly or dissociate quickly or easily), and elicit some of
>the second message, but not as efficiently as a strong agonist, thus the net
>response for 1 binding event is less (ie less depolarization or less cAMP
>being produced as examples).  This is dogma for membrane bound receptors.
>The AhR is a cytoplasmic receptor that binds the agonist (TCDD as one of
>many examples0, then binds another factor (ARNT) (I have seen lit evidence
>for this in the cytoplasm, but more in the nucleus - I don't know where that
>arguement/debate stands at the moment), then binds to it's DNA receptor,
>then elicits a change downstream.  This is a much more complicated series of
>events compared to  a membrane receptor.  A weaker agonist, or partial
>agonist (which means really that it doesn't bind as strongly or elicit as
>strong a response as the ligand that the investigator is studying, usually
>the endogenous chemical, sometimes (as here) not) could be "weaker" because:
>-it doesn't bind as quickly to the AhR in the cytoplasm
>-it dissociates more quickly from the AhR, maybe even before translocating
>to the nucleus
>-it prevents (partially or otherwise) ARNT binding
>- it inhibits or doesn't bind as well (as a complex) to the DRE - the DNA
>receptor
>-it (as a complex) dissociates more quickly from the DNA receptor.
>-it only binds to selective DNA receptors (that's possible too).
>
>Much more complex.
---

>
>As to mutations - by all evidence I have seen, TCDD is not a direct mutagen,
>especially not by directly damaging DNA when it binds to the DNA.  It is not
>an interchelator, or a base-changer, or any of those.  All evidence for
>carcinogenicity that I have seen stems from generation of oxygen radicals
>and peroxisome proliferation, which provides the mutagenicity.  I check this
>yearly, since it's always an issue in Tox class.  I did not teach tox this
>year, so my checking is just over a year old.  Evidence for direct
>genotoxicity may have surfaced in the past year, but I don't think so.
--------------------


Consonant w/ what I know.  But my question was could TCDD, this
non-genotoxin (ie non DNA mutagen), cause DNA mutations indirectly (by its
presence physically interferring w/ the faithful replication of DNA)?

Similarly, regarding David's response, it's not TCDD's effects during
transcription I was wondering about, but during replication.  I suppose
there is some potential for DNA damage from its presence duing
transcription as well, but the observations that it induces genes to
sucessfully create (transcribe) various proteins perhaps means it is not
damaging DNA--at least not those particular genes).  Starting to sound like
no one has investigated the physical state of DNA during rest,
transcription or replication if TCDD is glommed onto it--could be an
interesting area of study!  Thanks for your explanation of Kd (conversion:
your rough threshold of 6 pMoles of TCDD in a solution of water being
2ng/kg is a concentration of 2 ppt (ignring the complication of the complex
media it's dissolved in).

Thanks