Putting this up here will help me keep the issues, with the chiral carbons in reduced folates, straight. The problem with prescription leucovorin (folinic acid) used to be (and still is in the U.S.) that it was provided as racemic leucovorin (50 percent L-leucovorin, which is (6S)-folinic acid or levoleucovorin and is the biologically-identical diastereomer, and 50 percent D-leucovorin, which is (6R)-folinic acid, the unnatural diastereomer). Now, in Europe, I think, L-leucovorin, the purified diastereomer, is available. But the problem with the use of an unnatural diastereomer is that it's biologically inactive or less active and could potentially cause a folate binding protein to become immunogenic. I think this hasn't ever been demonstrated, and I bet that the hypersensitivity responses to leucovorin are the result of allergenic substances in the vehicle used for intravenous injections. Actually, here's an abstract from a conference that talks about hypersensitivity reactions to oral leucovorin (http://www.nursinglibrary.org/Portal/main.aspx?pageid=4024&pid=18574). I have my doubts about those hypersensitivity reactions to oral leucovorin. This abstract (I'm posting the google scholar search, because the url of the direct link is 50 pages long: http://scholar.google.com/scholar?q=%22Two+cases+of+allergy+to+leucovorin%22&hl=en&lr=) says that the patients were able to tolerate i.v. leucovorin after taking leucovorin orally, to induce oral tolerance (I think oral tolerance is mediated by IgA production in the intestinal tract). This is the type of thing I'm talking about, but this article basically "exonerates" leucovorin, at least in this specific case, by showing that this bizarre allergy was actually to folic acid (which has only one chiral carbon on its L-glutamic acid moiety):
http://www.ncbi.nlm.nih.gov/pubmed/10932085
That article is bizarre, because folic acid has no chiral carbons on its pterin moiety. So the person would be allergic to all folic acid, including folic acid from foods. But then the authors say that folate polyglutamates in food would not have the potential to become immunogenic? I don't think all the folates in food exist as polyglutamates. I read through that article, and the person developed a skin rash, like hives. If you develop hives or skin itching, reliably, following anything, I would talk to your doctor. There tends to be a sign of that sort of idiosyncratic reaction. Let me see if I can find a reference showing that not all naturally-occurring folates are polyglutamylated. Well, I don't even need to, because folic acid that's added to tons of different foods, as fortified folic acid, is definitely not polyglutamylated. The concern with reduced folates is not the degree of polyglutamylation but with the unnatural geometry around the chiral carbon.
I think there would be some kind of sign of a hypersensitivity reaction to something like methylfolate, though, because those types of allergies, to drugs or other compounds covalently bound to plasma proteins or cellular proteins, tend to cause allergic symptoms like shortness of breath, hives, itching, etc. But, as an example, I saw this article saying that castor oil in suspensions of phylloquinone (vitamin K1), used only to treat overanticoagulation due to warfarin, turned out to be the cause of hypersensitivity reactions to the injections. But it's still worth watching for those symptoms.
But that's the rationale for using only (6S)-5-methylfolate (the "L-methylfolate" diastereomer), to avoid those issues. L-methylfolate is actually available over-the-counter now, and I don't want to mention the brand names. But that's the way things work these days, that one pharmaceutical company will sell a preparation to the industry as a whole. It's complex to separate diastereomers, and one wouldn't want a product with impurities, etc. There would probably still be advantages to getting it by prescription, and a person should always talk to his or her doctor about these things. But I saw that someone was selling racemic leucovorin over-the-counter, and that's why I mention the potential pitfalls with these things. The preparation of L-methylfolate containing the purified diastereomer apparently contains less than 1 percent of D-5-methylfolate. There's a theoretical possibility for some sort of sensitization, like that, with a tiny amount of D-5-methylfolate, but I doubt it would be an issue. If it did occur, I think there would be symptoms of it that would alert you and let a person talk to his or her doctor.
I don't feel like talking about the fact that naturally-occurring, N10-substituted, reduced folates have a 6R conformation around carbon-6 (and this conformational change occurs, during the enzymatic reaction, without a true chiral inversion, from what I can tell), and so that's another issue that makes the stereochemistry confusing here.
No comments:
Post a Comment