liver, ammonia, kidney, urea question & system

Discussion in 'Biology & Genetics' started by Billy T, Feb 12, 2008.

  1. Billy T Use Sugar Cane Alcohol car Fuel Valued Senior Member

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    A failed liver is death. It converts ammonia accumulating into the blood into urea and That then leaves the body via the kidneys. Does the liver dump the urea it made back to the blood or send it more directly to the kidneys?

    The tiny company, HepaLife, in which I have a small finacial interest, has a patented cell line (from pig's livers) that continue to live and function. They are making an artifical liver. Personnally I think one of it main first commercial uses will be by developers of drugs. Very many fail to get their drug thru to market because after spending millions in clinical trials they learn it damages the liver. Testing on Hepalife's machine, once it is proven to be a realistic liver, will save millions for many. Here is some of their latest infromation:

    "... The performance of our bioartificial liver device is exciting. The rate of ammonia reduction achieved mainly via the natural urea cycle is an important step towards successful clinical application,” continued Mr. Menzler. “Furthermore, the ability of our cells to produce substantial amounts of urea while maintaining liver-like function, and preserving liver cell-like characteristics, all clearly establish the superior performance of our PICM-19 cell line inside our bioartificial liver.”

    Intended for the treatment of liver failure, the HepaLife™ Bioartificial Liver device consists of three basic components: (1) a plasma filter, separating the patients blood into blood plasma and blood cells; (2) the bioreactor, a unit filled with the patented PICM-19 liver stem cell line which biologically mimics the liver’s function; and (3), the HepaDrive™, a perfusion system for pumping the patient's plasma through the bioreactor while controlling gas supply and temperature for best possible performance of the cells.

    Incorporating the PICM-19 cell line, HepaLife is developing the first-of-its-kind bioartificial liver. HepaLife's bioartificial liver currently under development, is designed to operate outside the patient's body. The bioartificial liver is envisioned to mimic important functions of the human liver by circulating the patient's blood inside the device, where it is exposed to HepaLife's patented PICM-19 liver stem cells, thus processing the patient's blood-plasma by removing toxins, enhancing metabolic function, and ultimately, imitating the liver's natural function. ..."

    " ... HepaLife’s bioartificial liver reduced ammonia levels by 75% within less than 24 hours. Published in-vivo {in animals with NH3 added to blood, I think} clinical data of other systems utilizing liver cells other than HepaLife’s patented PICM-19, have only reported ammonia reduction levels between 0 to 44%. ..."

    From:
    http://news.morningstar.com/newsnet/ViewNews.aspx?article=/BW/20080211005461_univ.xml

    I started a thread about NH3 as a way to store hydrogen for mobile fuel in chemisty section and recently learned that Urea has been suggested for this also. See:
    http://www.sciforums.com/showpost.php?p=1737225&postcount=48

    I would like to understand more about the production of ammonia and urea by biologic system. Comments?

    One thing I have learned was that the "vitalist idea" (There is something special about molecules made by living organism) was first shot down by the synthesis of urea from inorganic chemicals, in contradiction to theory.
     
    Last edited by a moderator: Feb 12, 2008
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  3. draqon Banned Banned

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    great...first pig liver, than crocodile's heart, chimpanzee lungs, soon we want to be human.
     
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  5. Billy T Use Sugar Cane Alcohol car Fuel Valued Senior Member

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    It will only be a large external machine, sort of like kidney dialysis machines, (at least for many years.)
     
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  7. S.A.M. uniquely dreadful Valued Senior Member

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    Ammonia:

    Biological organisms can fix and utilise nitrogen in the form of amino acids and produce ammonia, the final breakdown product of amino acid metabolism. Ammonia levels can be increased by high intensity physical exercise (more amino acid breakdown), high protein diets (more amino acids to breakdown) and liver dysfunction (slow removal of ammonia generated through metabolism).

    Urea:

    Ammonia (NH[sub]3[/sub]) is converted to urea in the liver cells (called hepatocytes) through the urea cycle.

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    The liver transfers the urea to the bloodstream. When blood passes through the cells of the kidney (called nephrons), the urea is preferentially filtered out and passes into the filtrate, which is then condensed to urine.


    Blood enters the nephrons glomerulus through the afferent arteriole, it passes through the network of capillaries and is filtered, then passes out again through the efferent arteriole. The filtrate is collected and passed into the proximal convoluted tubule. Water and essential minerals are reabsorbed while wastes are passed into the collecting tubule and hence into ureter.

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    Last edited: Feb 13, 2008
  8. Billy T Use Sugar Cane Alcohol car Fuel Valued Senior Member

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    Thanks SAM - that was great. Some questions about the Urea cycle:

    Where does the "N-acetyl glutimate" come from?

    What happens to the fumaric acid that is co-produced with the urea?
    Into the blood also, I assume, but that sounds worse that the ammonia the cycle is removing to me in my ignorance about all this.

    Perhaps it is transformed somewhere into the aspartic acid which is also an input to the cycle? If not where does that come from? This is especially interesting to me as I think that HepaLife's "liver machine" would need it to be supplied also. Perhaps that may be a "show stopper" in practice?

    Although I knew that ammonia was essential (or nearly so) for plants your first statements make me wonder if some small amount in the blood is useful in animals also for the synthesis of proteins (actually amino acids, I bet) that are not present in their diet?
     
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  9. S.A.M. uniquely dreadful Valued Senior Member

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    This compound is made from acetyl Coenzyme A aka Acetyl CoA, which is obtained in the course of energy metabolism from carbohydrates, fats and proteins and glutamate, which is a nonessential amino acid (ie it can be made in the body and does not need to be provided from the diet)
    Correct. The fumaric acid or fumarate is converted to malic acid by fumarase enzyme; malate is converted to oxaloacetate which is transaminated to aspartate, which goes back into the urea cycle

    I do not think ammonia is used directly to synthesise amino acids, most nonessential amino acids are made from other amino acids, the essential amino acids are the ones that cannot be synthesised de novo.

    However, after production of ammonia from glutamine, the resultant compound, alpha ketoglutarate can be degraded to bicarbonates and forms an essential component of buffers in the blood.

    Just let me know if I am giving too much info

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  10. Billy T Use Sugar Cane Alcohol car Fuel Valued Senior Member

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    No, just right (at least for me) Thanks again.

    One small question more. (Motivated by wanting to better undestand Hepalife's machine's processing biochemistry.):

    OK., now I know:
    "fumarate is converted to malic acid by fumarase enzyme; malate is converted to oxaloacetate which is transaminated to aspartate,"

    but that means the process needs a supply of fumarase enzyme to close this loop adjacent to the urea cycle. (Shown in your drawing as "open" at the bottom of the urea cycle circle.) Where does it come form?

    Is it likely to be in adequate supply in the blood of a patient who needs the periodic aid of an artificial liver? I.e. do liver cells (especially those that are from a pig) close this "fumarate to aspartate" cycle or are some other body cells needed? I.e. if there is adequate fumarase enzyme in the sick patient's blood and the chemistry of this "fumarate to aspartate" cycle either is done only with liver cells or completly extra celular, then it should not be a problem for Hepalife's machine (assuming the fumarase enzyme can get thru their barrier keeping the much larger circulating plasma cells out. I.e. pass thru with the NH3. I bet that is the case as I think enzimes are relative small compared to the circulating cells they want to keep out of their machine.) Any comments?
    -----------------
    slightly related subject:
    I take occasionally, especially when exerscise is soon to follow: BCAAs Valina, ios leucina and Leucina (with B6) as have read older peopl's mussle loss is resisted with thier aid. Have a ref. if you want) are they essential or nonessentail amino acids?
     
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  11. S.A.M. uniquely dreadful Valued Senior Member

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    Fumarase is an enzyme that is also required for the fumarate to malate conversion in the Krebs, TCA or Citric acid cycle. This is the cycle of cellular respiration in which two carbons (originating from acetyl CoA, from carbohydrates and fats or proteins) are converted to carbon dioxide, with the generation of energy in the form of ATP. This process (which requires oxygen) takes place in all aerobic cells.


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    Krebs cycle

    So one would expect fumarase to be an inducible enzyme (ie gene expression of the enzyme induced by presence of increased amounts of substrate) which would function under feedback regulation by the product.

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    branched chain amino acids (leucine, isoleucine and valine) are all essential amino acids. ie cannot be produced de novo/

    An easy mnemonic to remember the EAAs

    Mett Vil Phly

    Methionine, Tyrosine, Tryptophan, Valine, Isoleucine, Leucine, Phenyl alanine, Lysine.

    Thats 8 out of the 20 that are a part of proteins.

    Besides the bcaa's Vitamin D has also been known to prevent muscle loss with age (as well as bone loss)
     
    Last edited: Feb 13, 2008
  12. Billy T Use Sugar Cane Alcohol car Fuel Valued Senior Member

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    Thanks again, but this is getting tough for me and I am not sure you have answered my basic questions. I guess "inductible" plus your "gene expression" means that most cells have the information to make the fumarase enzyne, but still not sure of this.

    Also I suspect that the version of the enzyme that pig liver cells make may not be identical to human made, but probably will still meet the needs of the ammonia conversion to urea cycle. This leaves mainly the concern about the quantity available in the plasma cell free fluid that contains the NH3 the pig liver cells are imersed in and working on. I.e. will there be enough, either because it passes thru the filter that keeps the larger plasma cells out of the artifical liver OR because it is automaticly made, as needed, by the pig liver cell line?

    There might be a problem if the Ammonia is in the extra cellular fluid and the enzyme is only inside the cells. I do not know, but suspect that the krebs & urea cyckles take place inside the cells, not in the extra cellular fluid, but even if true, probably the ammonia can get inside too and the urea produced can then get back out thru the cell wall into the clear fluid and eventually back in to the blood and then get, via the kidney, into the urine and be discharged.

    I do not know what hepalife provided to their Pig liver cells. If it was just clear Ringer's solution with NH3 and the enzyme added then their claimed 75%conversion of ammonia to urea in 24 hours, may not be worth much, until they start with sick patient's blood, get the enzyme and NH3 thru the filter (or at least the NH3 of the blood thru, if the pig cells making the enzyme is ok).

    I am not sure I am making my concerns clear. I want to know what a realistic demonstration of a potentially functional artificial liver device would be. Thus far, from what I have learned from you it seems that the NH3, the Enzyme and living liver cells to run (presumably inside them) the urea cycle is the basic requirement. I think there also must be a suitable barrier that passes NH3 and the enzyme, if it is not made by the pig liver cells (an of course the urea made back out later) while keeping the gross plasma cell out of the machine.

    Have you ever thought about what is required to try to make an artificial liver? Have any idea how long it would be before you needed to revisit the machine, it you were a "couch potatoe" (little exercise) and went on a strictly vegitarian diet? I.e. Few complex proteins broken down to make the NH3 build up rapidly in the blood. Could you go a week or two and not get too sick from excess NH3 in the blood? (By sort of like a diabetic helping to keep the blood sugar under control via control of diet, but avoid excessive exercise also.)
     
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