Discussion of Some Issues, Reported in the Literature, Related to the Potential for Contamination in Creatine Supplements

I already discussed this, but I thought I'd mention it here. About 2-3 weeks ago, I switched to a brand of supplemental creatine monohydrate that I hadn't taken in a long time and developed objective and recognizable manifestations of a hypersensitivity reaction to some constituent of that supplement. In my opinion, the brand was contaminated with one or more of the compounds that researchers have sometimes identified in creatine preparations [(http://scholar.google.com/scholar?q=contaminant+%22creatine%22+supplement+OR+commercial&hl=en&as_sdt=2001&as_sdtp=on); (http://scholar.google.com/scholar?hl=en&q=%22creatine%22+cyanoguanidine+OR+dicyandiamide+OR+dihydrotriazole&as_sdt=2000&as_ylo=&as_vis=0)]. I can reasonably rule out a contribution of the excipients in the product, given that I, prior to this incident, had taken another supplement from the same brand for a long time and had experienced no hypersensitivity reaction from the same excipients in that supplement. I actually took this brand of creatine about two or three years ago, for a relatively brief interval of time, and felt strongly, then, that it was contaminated. In my opinion, one or more guanidino/guanidinium or azo-/azide-based contaminants may have led to the formation of covalent adducts on various proteins and produced the hypersensitivity reaction. The symptoms resolved, mostly, within 12-24 hours of switching back to the brand I'd previously taken. I take a very small dose of creatine, and I've discussed the potential for adverse effects from metabolites (not contaminants) of creatine in many past postings on this blog. But many people would not be able to recognize signs of hypersensitivity reactions or make the connection, etc. I see at least one article, in one of those searches I linked to, that sounds like it could also have been a result of an "allergic"/autoreactive hypersensitivity reaction, in which there's an antibody response or even cytotoxic T-cell response, in more extreme cases, to a covalently-bound compound (such as a drug or drug metabolite). One explanation for this type of thing is that free drugs tend to be too small to be immunogenic but can sometimes become immunogenic when covalently bound (or, less commonly, tightly or "pseudoirreversibly") to the larger structure of the protein or other macromolecule, such as DNA. Many guanidinium compounds are well known to be reactive toward the formation of covalent adducts, [Lu et al., 2004: (http://www.unm.edu/~dd39/117.pdf); (http://scholar.google.com/scholar?hl=en&q=nucleophilic+adduct+guanidinium+OR+guanidino&as_sdt=2000&as_ylo=&as_vis=0)] and there are all sorts of reactions that can occur with reactive diamines and other nitrogen-containing compounds in vivo [Kalgutkar et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12093357)]. One could look at some of the other side effects, including rhabdomyolysis and interstitial nephritis (http://scholar.google.com/scholar?hl=en&q=%22creatine%22+supplement+rhabdomyolysis+OR+nephritis&as_sdt=2000&as_ylo=&as_vis=0), associated with the use of creatine and say that hyperosmotic stress, due to the increase in extracellular fluid volume and electrolyte-derangements that the use of high-dose creatine has been associated with, or creatine-derived creatinine or formate or formaldehyde or some strange, semicarbazide-sensitive-amine-oxidase-derived nitrogen-containing compound was to blame in a given case, but another possibility is that contaminant-induced hypersensitivity reactions produced some of those cases of rhabdomyolysis or interstitial nephritis. Drug-induced (as in xenobiotic-induced) hypersensitivity syndromes are known to be major causes of interstitial nephritis (http://scholar.google.com/scholar?hl=en&q=interstitial+nephritis+drug+hypersensitivity&as_sdt=2000&as_ylo=&as_vis=0) or rhabdomyolysis, individually (http://scholar.google.com/scholar?hl=en&q=rhabdomyolysis+drug+hypersensitivity&as_sdt=2000&as_ylo=&as_vis=0). A hypersensitivity syndrome could account for the report of reversible liver dysfunction in a person who had been taking creatine (or who had been taking non-creatine guanidino or azo -containing compounds, etc.) [(http://hardcorephysiologyfun.blogspot.com/2009/04/expression-of-creatine-kinase-by.html);(http://hardcorephysiologyfun.blogspot.com/2009/04/report-of-liver-dysfunction-or-damage.html)]. Why do the supposed hypersensitivity reactions to some creatine-containing supplement preparations appear to not be characterized by the kinds of wild and devastating qualities that drug-induced hypersensitivity reactions can be characterized by? One possibility is that there's thymic tolerance or acquired tolerance to protein adducts, formed as byproducts of normal rates of reactive oxygen species formation, etc., of endogenous guanidinium compounds and that the tolerance causes the xenobiotic-specific antibody response to be dampened or offset by the presence of antibodies to guanidinoacetyl protein adducts, or something like that, that cross-react with the xenobiotic-guanidium-containing adducts, etc. Maybe the abundance of endogenous guanidinium-containing adducts means that there's a high "dose of antigen," in the form of adducts of endogenous guanidino/guanidinium compounds, and that this favors the development of Th2-type responses to some xenobiotic adducts of guanidino compounds. Or maybe other mechanisms could account for the effects, etc. In any case, these are just my opinions. I should mention that covalent adducts/conjugates of drugs to proteins are thought to be a major, if not the major, cause of drug-induced liver injury, and the adducts or conjugates can form by lots of different mechanisms. There are endogenous molecules, such as some geometric isomers, I guess, of bilirubin, that can become covalently bound to proteins and become mildly immunogenic, etc. And protein tyrosine nitration and all sorts of other covalent modifications of proteins can occur normally. But there's likely to be relatively significant immune tolerance to proteins with nitrotyrosine residues, etc. Additionally, some types of drug-protein adducts are much more wildly immunogenic than others. One interesting question is why acetyl esters of endogenous compounds or of, for example, lipid-soluble vitamins don't seem to cause hypersensitivity reactions (apparently not, in my opinion). Maybe the covalent adducts are formed, via O-to-N acyl migration reactions or anomeric shifts of acyl glucuronides or reactions of acyl-CoA thioesters or other transesterification reactions or whatever other chaotic reactions, but are not immunogenic. There may be so many acetylated proteins, formed during protein acylation reactions, etc., or uridylylated RNA molecules or uridylyl or acyl enzyme intermediates that most or all of the possible neoantigens are tolerogenic or not immunogenic. I would guess that a random adduct of a non-xenobiotic would be less immunogenic than a random adduct of a xenobiotic, but that's just my guess. Another point I'd make is that people can be given the impression that drug-induced adverse effects are random, unpredictable, all-or-nothing events that can just be lumped together into a big heap of vagueness and bewilderment, etc. In many cases, the mechanisms underlying some of the potential adverse effects of a drug have been researched in tremendous detail and are reported in chemistry or pharmacology-related journal articles. It's usually possible to get a fairly clear picture of what's going on with a lot of these things, in my view, but that's just my opinion. And these are all just my opinions, obviously.