Re: Re oral MgSo4

[Guest guest]

,

> :

> This study may have been done on people ( or rats ) that

>had normal sulphate levels to begin with. Thus the body was

>just adjusting correctly. If the study had been done on

>people with low sulphate levels then things might be

>different.

The study was done on the sulfur deficient. Perhaps it would help to hear

a little extra info about how blood sulfate levels are regulated and then

more about that study.

Sulfate is too small to be retained when it passes through the glomerular

filter in the kidneys. Inorganic sulfate keeps travelling through the

kidney's tubes and ends up in the proximal (or near) tubules. In the

proximal tubules, there are sulfate transporters expressed on the cell

surface on the inside of the tube. These transporters reabsorb sulfate

from the fluid that will be called urine a little bit further down. As

soon as the diet becomes deficient in sulfur, the kidneys will very quickly

stop allowing the normal amount of sulfate to stay in the urine,. It

accomplishes that by upregulating the number of sulfate transporters in the

kidneys. This happens very quickly, and it is therefore very normal in

sulfur deficiency for there to be absolutely no sulfate showing up in the

urine because it ALL starts to be reabsorbed, as long as there are enough

transporters there to move that sulfate back into the tubule cells. This

describes a proper physiological response to low sulfate.

The situation commonly (not always) found in autism, is that there is an

excess loss of sulfate in the urine despite low body levels of

sulfate. Just to give you a sense of scale, the urinary sulfate in autism

is about double the loss in normal controls, but the range of differences

among people with autism is much broader. Clearly, some do not waste

sulfate, but others waste a LOT. If you suspect a sulfation problem

(autism or not) it is important to know this rate of loss, and especially

useful if it could be from a 24 hour specimen.

The odds are pretty great that if there is an excess loss of sulfate into

the urine, that something (and not necessarily the same thing in different

children) is generating a conflicting signal that is affecting the

expression of transporters in the kidney or affecting their ability to

function. These transporters are like the bucket brigade, but their number

on these cells is also regulated by potassium, Vitamin D, age (declining in

old age), by hormones like thyroid, growth hormones, glucocorticoids and

the hormones of pregnancy, and by ibuprofen and perhaps some other NSAIDS,

and the fairly new finding is that sulfate levels in the gut apparently

provide some regulation as well through some uncharacterized messenger.

Mercury that has arrived in the kidneys from other organs via the blood

apparently can keep the transporters from working properly even if they are

there in sufficient number. The presence of mercury would be expected to

cause the kidneys to be unable to pull the sulfate from the filtered fluid

back into kidney cells, and back into the blood. This reabsorption is very

important for maintaining sulfur levels. In AIDS, the amount of excess

loss of sulfate in the urine adds up to 4.4 pounds a year, and in that

disease, it is likely that the change in regulation is caused by some of

the excess immune factors caused by the rather unrelenting diseases people

with AIDS acquire. The specific mechanism for this lack of reabsorption of

sulfate has not been determined.

It was only this last year that I found the literature that suggests oral

sulfate isn't very useful in deficiency. Before then, , I was

occasionally giving my father mag sulfate that I put in capsules for days

when he refused a bath.

Glazenburg et al., 1983 was the first study I found on this. They knew,

from probably hundreds of studies (I'm sure I've seen a hundred) that

sulfotransferase activity of some types can be restored by IV infusion of

sulfate. (This is also a treatment for toxemia, by the way, which occurs

during the time in pregnancy when sulfate retention is supposed to be

upregulated.)

Anyway, Glazenburg et al. expected oral sulfate to work as well as IV

sulfate. This was reasonable to suspect because previous studies had

shown that labelled sulfate given by mouth or IV in very small amounts

ended up at about the same level of distribution in the blood within about

an hour and a half...in humans and was eliminated similarly after that. So

these other scientists induced sulfur starvation in rats by removing most

of the sulfur amino acid precursors from the diet. That means their diet

was very low in methionine and had as little as no cysteine (they tried

various levels). For one group, they added back the same amount of missing

sulfur in the form of inorganic sulfate added into the lab chow. They were

quite surprised to find that there was no significant change in blood

sulfate levels compared to the rats still on the sulfur depleted

diet. They had no explanation, but. fortunately, at the same time in these

rats, they were measuring the output of sulfate into the urine. They found

that every bit of added sulfate in the chow was matched by an INCREASED

disposal of sulfate in the urine in these rats who were sulfur deficient

and only getting sulfate in oral form.

There was at least one other study that found this phenomenon before a

scientist named Markovich discovered that oral sulfate must signal

the downregulation of sulfate transport in the kidneys by changing how much

of the tranporter was being made in the first place. These molecules have

a short life span on the cell surface.so need to be constantly

replaced. Some signal that works on the DNA/RNA level will cause there to

be fewer transporters formed that can travel to the surface of proximal

tubule cells and there act as the bucket brigade to bring sulfate back into

the blood. Again, this change in number can occur very quickly, so it is a

very responsive system.

> :

> This argument seems false to me because the reason the

>gradient would be reduced would be because there was

>sulphate in there. If the sulphate needed to be escorted

>through into the blood then this would be a significant factor,

>in that this transported sulphate might have to go to the liver

>before it got into usable form.??

I'm not totally sure I understand the question, but sulfate does not appear

to be taken up to any significant degree by the liver. The liver takes up

cystine and cysteine and methionine, and then exports glutathione, taurine

and sulfate. Sulfate does not become " useable " in the liver before it is

exported. It travels as inorganic sulfate, unless it has conjugated

something that has its own means of import into cells in sulfated form. It

is unclear what quantity of sulfate that gets into cells enters as a

conjugate of something else. Anyway, once inorganic sulfate is inside

cells, it MUST be converted into an activated state by combining with

adenosine and phosphate, forming a molecule called PAPS. Sulfotransferase

enzymes cannot use inorganic sulfate. They have to use this activated

PAPS. That means if sulfate is not getting into the cell to be made into

PAPS, it is really useless no matter how much inorganic sulfate you have in

your blood.

I've talked about kidney transporters, but all your other cells have to

have sulfate transporters that get sulfate across cellular membranes, both

inside and on the outside of the cell. I think there is a good chance that

mercury toxicity is having effects on sulfate transport in the

lysosome. Most studies that show where mercury collects in the cell (like

it collects in kidneys and brain on the " body scale " ) find that it is

densely present in lysosomes, which are the cell's recycling

centers. Defects in lysosomal sulfate recycling are seen in several

diseases with severe neurological consequences like the leukodystrophies

and the mucopolysccharidoses.

> :

> Maybe the liver's regulation of sulphate is out ?

The major place the liver may supply regulation is in the split of cysteine

sulfinic acid between the taurine and sulfate pathway. There is a lot to

that issue that I'm still trying to digest. It doesn't just happen in the

liver.

>How can

>such a simple thing get so difficult ?

Anything is difficult until you learn about it. After a while, it seems

elegant. Regulation is really a beautiful thing. There are lots of

safeguards to keep us from getting sick at the drop of a hat, and a lot of

redundancies to keep the shutdown of one part of the system from being so

devastating. That's why it seems from reviewing histories of children with

sulfation problems, that most have experienced a " multi-hit " scenario.

> I will still take the

>epsom salts at 400 mg/litre and if I decide to stop then I will

>cut down to 300, then 200, then 100, to give my body time

>to readjust.

I'm not really sure if the amount you are talking about would generate a

high enough concentration to trigger the " dump sulfate " signal. It would

be very nice to find out if you are experiencing sulfate loss through the

kidneys and to find out how much and how fast. Have you ever had that tested?

> The sulphur article fuels the fire here in this group.

That sort of surprises me!

>There seems to be some dispute as to what percentage of autistic

>people have high cysteine levels. I don't know how, or if, this

>can be determined.

Andy has said he has a good feel for this, and Dr. Waring has chronicled a

high cysteine to sulfate ratio, but that ratio may come more from the low

sulfate side than the high cysteine. I am not sure how cysteine, being one

value, relates to the whole sulfur picture since it is very unusual to

measure cysteine by itself and especially unusual to know how it changes in

relationship to at least a dozen other important sulfur-related

variables. I have applied with two other colleagues for a grant to

document this in a fairly large sample as well as a lot of other sulfur

issues. This will be looking at both children and adults with autism, and

I hope we get the money to do this. It would answer a lot of questions

about the differences that exist in this aspect of the chemistry, and this

would be done on a population that is not undergoing chelation yet. What

we would do that is different from Dr. Waring's work so far is that we have

the explicit goal of defining subtypes based on differences found in the

sulfate/sulfur chemistry and will examine issues of its regulation that are

suggested by other disease processes where this has been investigated more

thoroughly.

I want the data to talk for itself. So far, in the group of plasma amino

acid profiles I've gathered from listmates, the data is pretty eloquent

about there being big differences. I would just love to see plasma amino

acid profiles from listmates that were collected before starting chelation

and then again after.

Does this help a little, ? I appreciate your " can do " attitude!

At 09:54 AM 12/29/2001 +1030, you wrote:

>Thanks for a fine answer .

>

> :

> The only problem with that is that there seems to be a

>signal that is generated by oral sulfate which tells the

>kidneys to downregulate the reabsorption of sulfate by

>actually changing the number of sulfate transporters that are

>in the kidneys . Studies have shown that this downregulation

>seems to lead to no net gain in sulfate systemically because

>of how much more sulfate is spilled into the urine under this

>condition. The levels used in these studies may have been

>higher than what you state, and it has not been determined

>WHAT hormone r other regulator signals this change, so we

>don't know what the concentration has to be in the lumen or

>inside of the gut to trigger this " dump sulfate " signal.

>

>

> :

> The intestines do need more sulfate than other organs, but

>they need to get it from the basolateral side of cells. That

>means the side of cells that faces the blood supply. This

>means that the sulfate the cells needs is in the blood, and it

>may be driven by some sort of concentration gradient,

>making sulfate in the lumen of the gut interfere with sulfate

>absorption from the blood.

>

>

> :

> A study by Dr. Stipanuk at Cornell showed that in rats, to

>accomodate the gut's need for sulfate, the liver exports

>sulfate in large quantity into the blood, but all that sulfate

>seems to be taken up out of the blood by the intestinal

>system. So when blood levels of sulfate are low, it will

>apparently be the gut that goes suffering.

>

> Moses.

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