We know that the CFTR functions to transport GSSG and MT, in the form of Cu-thionein. I am still not sure about GSH, but it doesn't matter, because the glutathione cycle is extracellular as well as intracellular. And we know that this function is missing in CF, of course. But what does that mean? Can we see it in the pathology of this disease? 

Yes, we can. We are seeing it, in the metalloenzymes, including those that have both inhibitory sites that require metal chelation, and in those that require delivery of metals. The literature bears this out. The copper metalloenzymes Cu,zn-superoxide dismutase and cytochrome c oxidase are not as active in CFers as in normals. These enzymes are expressed in CF, but just as we see in the studies on marginal copper deficiency, the enzymes are not as active in CFers. As well, we have seen our first zinc metalloenzyme that, unlike some zinc metalloenzymes, such as calcineurin, that require chelation of the metal, require delivery of zinc: carbonic anhydrase, which has been shown to be inactive in CF. This enzyme is responsible for the movement of sodium bicarbonate (HCO3-) over the epithelial membrane, which is lacking in CF tissues. We can now explain it. 

We also know one of the major reasons for lipid peroxidation: the relationship between copper and glutathione peroxidase. I don't know exactly what is going on here, and I don't care to learn it any deeper, unless I absolutely have to, but the research on the relationship between these two compounds is very strong because it's stood the test of time, and of replication. And that research makes the statement that a copper deficiency leads to a lack of function (or statement; I don't know which, yet) of glutathione peroxidase. This would cause a lot of lipid peroxidation, and it is well known that CF patients lack selenium, which is a basic component of glutathione peroxidase. 

The most difficult part of this is chelation, and zinc-inhibited enzymes. I am not clear at all on if that is correct or not. When I look at CF pathology and I look at the functions of these enzymes, things are going backward. This usually means that I have something screwed up somewhere in my understanding of the function of the relevant enzymes (and the transcriptional transactivators). I hope that we don't need chelation. It would make things so much easier if we didn't. But, I think it is more likely, when I look at the effect of excess zinc on the pancreas, that I am right about the chelation of zinc Excess zinc's first target is the pancreas. And the gross pathology mirrors the gross pathology of the CF pancreas. 

Now that we have hit the metalloenzymes, I am sure we are going to turn up a few more. I am going to limit how many we write about though. We're definitely going to have to talk about the ones that I've named here, and of course, the phosphatases, which all require zinc for activity, and are definitely malfunctioning in CF. Hopefully, that's all that's necessary. Fortunately, at this point, we are being very, very specific and we have research to back up our hypotheses. 

There are two questions that we need answered: the chelation question, and the "inside/outside" thing. Think about it: you can't transport MT out of the cell. What does that mean intracellularly? Mostly, here, we've talked about delivery, and we've talked about the outside of the cell (the lactoperoxidase system of defense--ie., hypothiocyanate: copper thionein/GSH/cyanide and cu,zn-superoxide dismutase). But what about the inside? What happens here? Here, we know that we have cytochrome c oxidase, and this is where the transactivator Sp1, which requires zinc, and controls the statement of IL-10 lies--it must be located intracellulary because it's a DNA transactivator, and DNA is intracellular, of course. Let's look at that....... 

Sp1 requires zinc and cytochrome c oxidase requires copper. And the scenario is this: first, you have too much MT, just as you have too much GSH. And, of course, you have too much GSSG. The function of GSH is told zinc and copper. The function of GSSG is to knock them off of MT. So you have MT in the cell, and it's full, chock full of copper and zinc. It can't hold all of it, that's floating around in ionic form. Now, you have some copper efflux proteins, too, in the cell, and they're pretty important, because copper is toxic and the cell is going to make sure that it controls it. Even though copper has more of an affinity for MT than zinc does, the research shows that this doesn't matter. I suspect that this is because of redox environment in the cell, but I'll take the research at it's face, and not worry about it for now. The research shows that if you have excess copper, you don't have zinc deficiency. But if you have excess zinc, you do have copper deficiency. This is probably because the copper is effluxed through those copper channels that are mutated in Wilson's disease. So, you are full up with zinc, and pumping copper out like mad. 

This explains the lack of delivery of copper, intracellularly, to cytochrome c oxidase. But it doesn't explain Sp1, does it? Why is there a lack of zinc delivery to Sp1? Something is wrong here; the inside/outside question eludes me...