[Dioxin-l] Single molecule and statistics

[david bell]

Hi Ron
><snip>the statistical features of a toxin reaching its intended site?  We
>might guess that the rate of the two "finding" each other is proportional 
>to
>the product of their concentrations.  At large levels of dioxin in a system
>the rate of encounter will be high.  But its efficacy will fall in line 
>with
>lowering concentrations.

Several issues:
1) dioxin is highly insoluble in water, and so most dioxin in a cell will be 
in in cellular lipid, or bound to a hydrophobic site- it won't be available 
to bind the aqueous dioxin receptor.
2) the concentration of both dioxin (at picoMolar) and its receptor (very 
low, but I can get you the number) are both extremely low.
3) even if the dioxin-bound AhR gets into the nucleus, bear in mind that it 
is estimated that there are about 10 000 binding sites for an activated 
receptor in DNA- so the AhR has to 'sort through' all the rest of the DNA ( 
a process that is poorly understood), and find a real dioxin binding site 
that does something (eg activate P450).

let me be clear that I am not saying that dioxin doesn't work (it obviously 
does), but the above considerations influence how it works. Additionally, 
the Ah Receptor is known to bind dioxin with a Kd of approximately 6 
picoMolar. Binding of ligand to the receptor below 6 picomolar falls in the 
realm of receptor theory, which is fairly well understood.


>The excellent point raised by Diane Henshel about a nonzero rate of
>metabolic destruction then comes into play.  That process too should take
>place at a rate proportional to products of concentration, and will operate
>competitively with the toxic activity.

In humans, the half-life of TCDD has been estimated at 7 years; for the 
purposes of looking at effects like this, metabolism is negligible. In rats, 
2-3 weeks; but even so, a small proportion.
cheers
david


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