Guest guest Posted June 16, 2003 Report Share Posted June 16, 2003 I'm thinking about trying a cysteine supplement for my son, since he seems to be low in sulfur and probably doesn't get much cysteine in his diet. I have seen supplements labeled L-cysteine and N-acetyl- cysteine. What is the difference, and is one better than another? I may try to get a plasma cysteine test for him, but it will be another month before we will see the doctor who would order it for us. Is there any harm in trying some form of cysteine if it turns out to be something he doesn't need? Kat Quote Link to comment Share on other sites More sharing options...
Guest guest Posted June 16, 2003 Report Share Posted June 16, 2003 > I'm thinking about trying a cysteine supplement for my son, since he > seems to be low in sulfur and probably doesn't get much cysteine in > his diet. Do a plasma cysteine test and find out first. >I have seen supplements labeled L-cysteine and N-acetyl- > cysteine. What is the difference, and is one better than another? > > I may try to get a plasma cysteine test for him, but it will be > another month before we will see the doctor who would order it for > us. Is there any harm in trying some form of cysteine if it turns out > to be something he doesn't need? It is possible. If you are restrained any problems should abate within a week of stopping, but some people do have long term worsenings if they get too much at one time. > > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted June 18, 2003 Report Share Posted June 18, 2003 Kat, There seems to be a lot of differences in which form of sulfur children who need more sulfur will tolerate, and we are trying to learn what those differences mean, as far as what the underlying issues are in their biochemistries. It may be that a lot of the negative reactions to specific supplements come because the factors that work with those substances are themselves not appropriately available or primed for reactions or specific transport of those cofactor substances is not working properly, so they are not in the compartment where they need to be when they are needed. This methyl-B12 seems to be that sort of substance and thiamine may be as well. So, for the moment, which form of sulfur will help is a little hard to predict and the solution may involve something besides a sulfur compound. But, I would encourage those of you who have seen an obviously negative or obviously positive reaction to a sulfur supplement to join me on the sulfurstories list and tell your story there with enough detail so that we could spot different common patterns if possible. From what I have been told by Great Smokies about what their plasma cysteine test measures, I think it can be VERY misleading and seems to be taken as meaning far more than it can mean. Many different things might influence the numbers there. I took these concerns to an expert in glutathione and thiol trafficking who has done studies observing how thiol disulfide exchange influences the numbers that quantify sulfur compounds in the blood. He said exactly what I had been thinking about that test all along, that it doesn't tell you much that is useful at all...by itself, that is, ie., out of context with a lot of other testing. Now, I have to qualify that by saying that Andy has said here that he has the impression that those who have high values on that test tend to be the same people who have problems with sulfur supplements and/or sulfur foods. I respect that observation, but since it is so generalized, it needs to be followed up by much more investigation. In order to understand WHAT that observation means that is different about those children, we have to know what is happening with TRANSPORT out of the blood into various organs, and the expert basic scientists can help us understand how many possibilities could create that situation. I can say that the plasma cysteine test does not mean you have too much sulfur in your system because a blood test cannot tell you that...There is no correlation between these things measured in blood and inside tissues. So there are other things you would measure to get a more complete picture. There are a lot of well-characterized deficiency situations where the plasma thiols get elevated, the most obvious one being when GGT is not working well. Knockout mice for that enzyme end up with horrendous elevations of sulfur in their blood and urine, but their cells are starving for sulfur, and they cannot grow like they ought to. They do very well on N-acetylcysteine. From my own collection of plasma amino acid profiles from children on the spectrum, I can tell you that it is extremely rare to see cystine + cysteine above the control mean (which is what is measured on the plasma amino acid test that measures all the standard amino acids in free form). The Great Smokies Test is NOT measuring only these forms, but is measuring thiols in general, and I'm still trying to get them to tell me what lab procedure they are using because the interpretation of the test would be different depending on how the sample was handled before they did their counting. Even the numbers from the plasma amino acid test can be misleading, because I have found that the children on the spectrum who are within the reference range appear to have signs of being catabolic (extemely thin, not growing, some on feeding tubes), so that the cysteine and cystine that is keeping the cyst(e)ine within the reference range appears to be coming from breaking down muscle. Sulfur is so critical to life that catabolism of the muscles will occur when there is a critical need for sulfur, and there is no getting around that, apparently, and the status of the muscles may be a much better tool for assessment than anything you might measure in the blood! This is kind of like calcium. Blood calcium levels don't tell you as much as noting whether someone has osteopenia or osteoporosis. So highs and lows in the blood are most likely a trafficking issue, meaning that the body is changing how it is handling sulfur compounds in response to its perception of what is happening. Transport into cells may be broken or misregulated and it is very clear that the body has to have enough sulfur to keep this system working properly, because the managers of sulfur in the body need sulfur themselves! Many different things can influence these numbers in lab tests, and the explanation of what has happened is not likely to be the same for the exact same lab numbers. That is why it is necessary to know all the possibilities of what can influence the test before offering an interpretation. I think traditionally people have avoided L-cysteine because when sulfur deficiency symptoms show up, some of the time, cystine's transport into cells is hurting. Maybe that is not too likely in this population since cystine in the blood seems usually to be low. Since cysteine will bind another cysteine much more easily than binding glutathione or something else, and since it is so reactive that is unlikely to stay cysteine for long at all. The blood is NOT at homeostasis because of the influence of transporters on the relative levels of sulfur compounds. If cystine transport is hurting, raising free cysteine won't help unless you can fix the problem with cystine transport. If that is the problem with using cysteine, then one solution is taking glutamine. Glutamine transport is usually fine, and it can get into the cell, convert to glutamate, and then glutamate intracellulary can exchange for cystine extracellularly, so THAT makes the cystine transporter able to work and get the cystine into cells. So, the solution in that case is not sulfur at all, but glutamine! That's just an example to show that it isn't so simple that you can measure something in the blood and then take that something to fix things, or measure it to be high in the blood and assume it is too high in tissues. But, by far, the most successful way to get cysteine into cellls in the literature in a myriad of disease situations has been N-acteyl cysteine, and it uses a different transporter from cysteine and cystine in free form, but it is a transporter that is shared by other organic anions and works from the bottom side of cells. But, some children have problems with this supplement, which may suggest they could be having problems with this particular organic anion carrier. I've put an article below about its regulation. So, Kat, there are at least ten different forms of sulfur that may help boost the sulfur chemistry, and have worked effectively in some children, but in others they have caused problems. So I think the best advice at this point is to try to find a child whose history is closest to that of your own child and whose response to varioius supplements and interventions has been similar, and see what has worked for them and try what worked for them cautiously, always starting with a very low dose, and work up gradually to your target dose. And if you have a negative response to a supplement of sulfur, please come join us on sulfurstories and tell your tale. PS. This article below should also help us develop some needed balance to interpretations of the GSDL detox test, for if the organic anion carrier is in a different state of function, then it might change what showed up in the urine after that test, influencing the levels of what was measured in a way that may not reflect what is happening in the liver and other cells providing detoxification. Biochem Pharmacol. 2003 May 1;65(9):1393-405. Related Articles, Links [Click here to read] Modulatory effects of hormones, drugs, and toxic events on renal organic anion transport. Terlouw SA, Masereeuw R, Russel FG. Department of Pharmacology and Toxicology 233, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. The human body is exposed continuously to a wide variety of exogenous compounds, many of which are anionic compounds. In addition, products of phase II biotransformation reactions are negatively charged, viz. glucuronides, sulfate esters, or glutathiones. Renal transport of organic anions is an important defense mechanism of the organism against foreign substances. The combination of the rate of uptake and efflux and the intracellular disposition of organic anions in the proximal tubule determines the intracellular concentration and the nephrotoxic potential of a compound. Modulation of organic anion secretion is observed after exposure of proximal tubules to various hormones, and the subsequent receptor-mediated response is signaled by protein kinases. Transport of anionic compounds across the basolateral as well as the luminal membrane is modified by activation or inhibition of protein kinases. Protein kinase C activation reduces the uptake of organic anions mediated by the organic anion transporter 1 (OAT1/Oat1) and Oat3 and reduces Mrp2-mediated efflux. In addition, activation of protein kinase C has been shown to inhibit transport by the organic anion transporting polypeptide 1 (Oatp1) across the luminal membrane. Additional protein kinases have been implicated in the regulation of organic anion transport, and the role of nuclear factors in xenobiotic excretion is an emerging field. The physiological regulation of organic anion transporters may also be influenced by exogenous factors, such as exposure to xenobiotics and cellular stress. This commentary discusses the current knowledge of endogenous and exogenous influences on renal anionic xenobiotic excretion. PMID: 12732351 [PubMed - indexed for MEDLINE] Hepatology. 2000 Oct;32(4 Pt 1):740-9. Related Articles, Links [Click here to read] gamma-glutamyltranspeptidase-deficient knockout mice as a model to study the relationship between glutathione status, mitochondrial function, and cellular function. Will Y, Fischer KA, Horton RA, Kaetzel RS, Brown MK, Hedstrom O, Lieberman MW, DJ. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA. willy@... gamma-Glutamyltranspeptidase (GGT)-deficient mice (GGT(-/-)) display chronic glutathione (GSH) deficiency, growth retardation, and die at a young age (<20 weeks). Using livers from these mice, we investigated the relationship between GSH content, especially mitochondrial, and mitochondrial and cellular function. We found that the GSH content of isolated liver mitochondria was diminished by >/=50% in GGT(-/-) mice when compared with wild-type mice. Respiratory control ratios (RCRs) of GGT(-/-) mice liver mitochondria were </=60% those of wild-type mice primarily as a result of impaired state 3 respiration. Mitochondrial adenine nucleotide content was decreased by >/=40% in mitochondria obtained from GGT(-/-) mice. We observed a strong correlation between mitochondrial GSH content and RCRs. Even moderate decreases (<50%) correlated with adverse effects with respect to respiration. Electron microscopy revealed that livers from GGT(-/-) knockout mice were deprived of fat and glycogen, and swollen mitochondria were observed in animals that were severely deprived of GSH. Thus, GGT(-/-) mice exhibit a loss of GSH homeostasis and impaired oxidative phosphorylation, which may be related to the rate of adenosine triphosphate (ATP) formation and subsequently leads to progressive liver injury, which characterizes the diseased state. We also found that supplementation of GGT(-/-) mice with N-acetylcysteine (NAC) partially restored liver GSH, but fully restored mitochondrial GSH and respiratory function. Electron microscopy revealed that the livers of NAC-supplemented GGT(-/-) mice contained fat and glycogen; however, slightly enlarged mitochondria were found in some livers. NAC supplementation did not have any beneficial effect on the parameters examined in wild-type mice. PMID: 11003618 [PubMed - indexed for MEDLINE] At 11:44 PM 6/16/2003 +0000, you wrote: >I'm thinking about trying a cysteine supplement for my son, since he >seems to be low in sulfur and probably doesn't get much cysteine in >his diet. I have seen supplements labeled L-cysteine and N-acetyl- >cysteine. What is the difference, and is one better than another? > >I may try to get a plasma cysteine test for him, but it will be >another month before we will see the doctor who would order it for >us. Is there any harm in trying some form of cysteine if it turns out >to be something he doesn't need? > >Kat > > > >======================================================= > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted June 19, 2003 Report Share Posted June 19, 2003 , From your research, can you make us up a chart, showing us the different kinds of kids--symptoms etc. --and what form of sulphur is most effective for them? Barb Re: [ ] Cysteine supplementation > Kat, > > There seems to be a lot of differences in which form of sulfur children who > need more sulfur will tolerate, and we are trying to learn what those > differences mean, as far as what the underlying issues are in their > biochemistries. It may be that a lot of the negative reactions to specific > supplements come because the factors that work with those substances are > themselves not appropriately available or primed for reactions or specific > transport of those cofactor substances is not working properly, so they are > not in the compartment where they need to be when they are needed. This > methyl-B12 seems to be that sort of substance and thiamine may be as > well. So, for the moment, which form of sulfur will help is a little hard > to predict and the solution may involve something besides a sulfur > compound. But, I would encourage those of you who have seen an obviously > negative or obviously positive reaction to a sulfur supplement to join me > on the sulfurstories list and tell your story there with enough detail so > that we could spot different common patterns if possible. > > From what I have been told by Great Smokies about what their plasma > cysteine test measures, I think it can be VERY misleading and seems to be > taken as meaning far more than it can mean. Many different things might > influence the numbers there. I took these concerns to an expert in > glutathione and thiol trafficking who has done studies observing how thiol > disulfide exchange influences the numbers that quantify sulfur compounds in > the blood. He said exactly what I had been thinking about that test all > along, that it doesn't tell you much that is useful at all...by itself, > that is, ie., out of context with a lot of other testing. > > Now, I have to qualify that by saying that Andy has said here that he has > the impression that those who have high values on that test tend to be the > same people who have problems with sulfur supplements and/or sulfur > foods. I respect that observation, but since it is so generalized, it > needs to be followed up by much more investigation. In order to understand > WHAT that observation means that is different about those children, we have > to know what is happening with TRANSPORT out of the blood into various > organs, and the expert basic scientists can help us understand how many > possibilities could create that situation. > > I can say that the plasma cysteine test does not mean you have too much > sulfur in your system because a blood test cannot tell you that...There is > no correlation between these things measured in blood and inside > tissues. So there are other things you would measure to get a more > complete picture. There are a lot of well-characterized deficiency > situations where the plasma thiols get elevated, the most obvious one being > when GGT is not working well. Knockout mice for that enzyme end up with > horrendous elevations of sulfur in their blood and urine, but their cells > are starving for sulfur, and they cannot grow like they ought to. They do > very well on N-acetylcysteine. > > From my own collection of plasma amino acid profiles from children on the > spectrum, I can tell you that it is extremely rare to see cystine + > cysteine above the control mean (which is what is measured on the plasma > amino acid test that measures all the standard amino acids in free form). > The Great Smokies Test is NOT measuring only these forms, but is measuring > thiols in general, and I'm still trying to get them to tell me what lab > procedure they are using because the interpretation of the test would be > different depending on how the sample was handled before they did their > counting. > > Even the numbers from the plasma amino acid test can be misleading, because > I have found that the children on the spectrum who are within the reference > range appear to have signs of being catabolic (extemely thin, not growing, > some on feeding tubes), so that the cysteine and cystine that is keeping > the cyst(e)ine within the reference range appears to be coming from > breaking down muscle. Sulfur is so critical to life that catabolism of the > muscles will occur when there is a critical need for sulfur, and there is > no getting around that, apparently, and the status of the muscles may be a > much better tool for assessment than anything you might measure in the > blood! This is kind of like calcium. Blood calcium levels don't tell you > as much as noting whether someone has osteopenia or osteoporosis. > > So highs and lows in the blood are most likely a trafficking issue, meaning > that the body is changing how it is handling sulfur compounds in response > to its perception of what is happening. Transport into cells may be broken > or misregulated and it is very clear that the body has to have enough > sulfur to keep this system working properly, because the managers of sulfur > in the body need sulfur themselves! Many different things can influence > these numbers in lab tests, and the explanation of what has happened is not > likely to be the same for the exact same lab numbers. That is why it is > necessary to know all the possibilities of what can influence the test > before offering an interpretation. > > I think traditionally people have avoided L-cysteine because when sulfur > deficiency symptoms show up, some of the time, cystine's transport into > cells is hurting. Maybe that is not too likely in this population since > cystine in the blood seems usually to be low. Since cysteine will bind > another cysteine much more easily than binding glutathione or something > else, and since it is so reactive that is unlikely to stay cysteine for > long at all. The blood is NOT at homeostasis because of the influence of > transporters on the relative levels of sulfur compounds. If cystine > transport is hurting, raising free cysteine won't help unless you can fix > the problem with cystine transport. If that is the problem with using > cysteine, then one solution is taking glutamine. Glutamine transport is > usually fine, and it can get into the cell, convert to glutamate, and then > glutamate intracellulary can exchange for cystine extracellularly, so THAT > makes the cystine transporter able to work and get the cystine into > cells. So, the solution in that case is not sulfur at all, but > glutamine! That's just an example to show that it isn't so simple that you > can measure something in the blood and then take that something to fix > things, or measure it to be high in the blood and assume it is too high in > tissues. > > But, by far, the most successful way to get cysteine into cellls in the > literature in a myriad of disease situations has been N-acteyl cysteine, > and it uses a different transporter from cysteine and cystine in free form, > but it is a transporter that is shared by other organic anions and works > from the bottom side of cells. But, some children have problems with this > supplement, which may suggest they could be having problems with this > particular organic anion carrier. I've put an article below about its > regulation. > > So, Kat, there are at least ten different forms of sulfur that may help > boost the sulfur chemistry, and have worked effectively in some children, > but in others they have caused problems. So I think the best advice at > this point is to try to find a child whose history is closest to that of > your own child and whose response to varioius supplements and interventions > has been similar, and see what has worked for them and try what worked for > them cautiously, always starting with a very low dose, and work up > gradually to your target dose. And if you have a negative response to a > supplement of sulfur, please come join us on sulfurstories and tell your tale. > > > > PS. This article below should also help us develop some needed balance to > interpretations of the GSDL detox test, for if the organic anion carrier is > in a different state of function, then it might change what showed up in > the urine after that test, influencing the levels of what was measured in a > way that may not reflect what is happening in the liver and other cells > providing detoxification. > > Biochem Pharmacol. 2003 May 1;65(9):1393-405. Related Articles, Links > [Click here to read] > Modulatory effects of hormones, drugs, and toxic events on renal > organic anion transport. > > Terlouw SA, Masereeuw R, Russel FG. > > Department of Pharmacology and Toxicology 233, University Medical > Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. > > The human body is exposed continuously to a wide variety of exogenous > compounds, many of which are anionic compounds. In addition, products of > phase II biotransformation reactions are negatively charged, viz. > glucuronides, sulfate esters, or glutathiones. Renal transport of organic > anions is an important defense mechanism of the organism against foreign > substances. The combination of the rate of uptake and efflux and the > intracellular disposition of organic anions in the proximal tubule > determines the intracellular concentration and the nephrotoxic potential of > a compound. Modulation of organic anion secretion is observed after > exposure of proximal tubules to various hormones, and the subsequent > receptor-mediated response is signaled by protein kinases. Transport of > anionic compounds across the basolateral as well as the luminal membrane is > modified by activation or inhibition of protein kinases. Protein kinase C > activation reduces the uptake of organic anions mediated by the organic > anion transporter 1 (OAT1/Oat1) and Oat3 and reduces Mrp2-mediated efflux. > In addition, activation of protein kinase C has been shown to inhibit > transport by the organic anion transporting polypeptide 1 (Oatp1) across > the luminal membrane. Additional protein kinases have been implicated in > the regulation of organic anion transport, and the role of nuclear factors > in xenobiotic excretion is an emerging field. The physiological regulation > of organic anion transporters may also be influenced by exogenous factors, > such as exposure to xenobiotics and cellular stress. This commentary > discusses the current knowledge of endogenous and exogenous influences on > renal anionic xenobiotic excretion. > > PMID: 12732351 [PubMed - indexed for MEDLINE] > > Hepatology. 2000 Oct;32(4 Pt 1):740-9. Related Articles, Links > [Click here to read] > gamma-glutamyltranspeptidase-deficient knockout mice as a model to > study the relationship between glutathione status, mitochondrial function, > and cellular function. > > Will Y, Fischer KA, Horton RA, Kaetzel RS, Brown MK, Hedstrom O, > Lieberman MW, DJ. > > Department of Biochemistry and Biophysics, Oregon State University, > Corvallis, OR, USA. willy@... > > gamma-Glutamyltranspeptidase (GGT)-deficient mice (GGT(-/-)) display > chronic glutathione (GSH) deficiency, growth retardation, and die at a > young age (<20 weeks). Using livers from these mice, we investigated the > relationship between GSH content, especially mitochondrial, and > mitochondrial and cellular function. We found that the GSH content of > isolated liver mitochondria was diminished by >/=50% in GGT(-/-) mice when > compared with wild-type mice. Respiratory control ratios (RCRs) of GGT(-/-) > mice liver mitochondria were </=60% those of wild-type mice primarily as a > result of impaired state 3 respiration. Mitochondrial adenine nucleotide > content was decreased by >/=40% in mitochondria obtained from GGT(-/-) > mice. We observed a strong correlation between mitochondrial GSH content > and RCRs. Even moderate decreases (<50%) correlated with adverse effects > with respect to respiration. Electron microscopy revealed that livers from > GGT(-/-) knockout mice were deprived of fat and glycogen, and swollen > mitochondria were observed in animals that were severely deprived of GSH. > Thus, GGT(-/-) mice exhibit a loss of GSH homeostasis and impaired > oxidative phosphorylation, which may be related to the rate of adenosine > triphosphate (ATP) formation and subsequently leads to progressive liver > injury, which characterizes the diseased state. We also found that > supplementation of GGT(-/-) mice with N-acetylcysteine (NAC) partially > restored liver GSH, but fully restored mitochondrial GSH and respiratory > function. Electron microscopy revealed that the livers of NAC-supplemented > GGT(-/-) mice contained fat and glycogen; however, slightly enlarged > mitochondria were found in some livers. NAC supplementation did not have > any beneficial effect on the parameters examined in wild-type mice. > > PMID: 11003618 [PubMed - indexed for MEDLINE] > > > At 11:44 PM 6/16/2003 +0000, you wrote: > >I'm thinking about trying a cysteine supplement for my son, since he > >seems to be low in sulfur and probably doesn't get much cysteine in > >his diet. I have seen supplements labeled L-cysteine and N-acetyl- > >cysteine. What is the difference, and is one better than another? > > > >I may try to get a plasma cysteine test for him, but it will be > >another month before we will see the doctor who would order it for > >us. Is there any harm in trying some form of cysteine if it turns out > >to be something he doesn't need? > > > >Kat > > > > > > > >======================================================= > > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted June 23, 2003 Report Share Posted June 23, 2003 Barb, If you look at the AutismOne website, you can download my lecture there, and that gives a lot of specifics in a graphic form that will be easier to understand than anything I could write here. The sulfur chemistry is complicated enough that my impression is that we might find as many as twenty different " primary " weaknesses in the sulfur system that possibly could be affecting different children with autism. But, right now, I'm VERY unhappy with the testing that is available, because a lot of labs are not aware of what you have to do to assure that you are measuring what you think you are measuring, and there have been many animal stuides that have used other tests to identify differences that CAN be measured in the laboratory. Unfortunately, those tests aren't available commercially. I'm been talking to a bunch of lab directors to see if we can do something about that, but for right now, we have to work with the tests that ARE available. But, I need to learn more from parents about how diverse are reactions to sulfur supplements, and for that, I really rely on the parents for input. I wouldn't expect that every sulfur system problem would be represented in our population, but neither could I assume " never " . In two conferences where I've attended in the last year or two, I've been really surprised that the hosts had issues in their families that probably were a genetic fragility in the sulfur system, and each may require some " customization " of approach, and an approach that would be really different from some perceived norm. How many others might there be with this sort of issue? In any environmental exposure, the first people to be " selected " by the exposure are the ones who have a genetic fragility or other risk from a different environmental situation. But if I am remembering right, I think my slides do include lists of symptoms of biotin and taurine deficiency, and neurological issues that would be affected by sulfate deficiency. For more details, also, Barb, I would suggest subscribing to sulfurstories and reviewing through the archives, especially searching on any subject you think is relevant to your child. At 09:01 AM 6/19/2003 -0500, you wrote: >, > >From your research, can you make us up a chart, showing us the different >kinds of kids--symptoms etc. --and what form of sulphur is most effective >for them? >Barb Quote Link to comment Share on other sites More sharing options...
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