One thing I was going to mention is that an excessive intake of inorganic phosphate, alone or in combination with oral purine nucleotides, could conceivably interact with prescription or nonprescription drugs that are substrates of organic anion transporters (OAT's) or multidrug resistance (MDR) protein transporters. The main types of drug-drug interactions that are given attention in the literature are the interactions that involve the noncompetitive inhibition, induction, or competitive inhibition of cytochrome P450 enzymes. But another type of interaction that would be more difficult to predict or even measure could be the competition of two substrates for export, across the canalicular, or apical, membranes of biliary epithelial cells, into the bile. Urate and phosphate can compete for export into the blood or bile by OAT's on the plasma membranes of different cell types in the liver, and bilirubin (http://scholar.google.com/scholar?q=bilirubin+%22organic+anion%22&hl=en), bile acids (http://scholar.google.com/scholar?hl=en&q=%22bile+acids%22+%22organic+anion%22), and other compounds are also substrates of various OAT's. A lot of different drugs are also substrates of OAT's (http://scholar.google.com/scholar?q=drugs+transport+%22organic+anion%22&hl=en) and might compete with urate or phosphate or xanthine, for example, conceivably, for export into the bile. It's unlikely that these interactions would be significant, in my opinion, except at high or excessive dosages of uricogenic purines or inorganic phosphate or in people who have liver or kidney disease. As I've mentioned in past postings, however, some neuraminidase inhibitors and other drugs or metabolites of drugs that are excreted unchanged or otherwise eliminated primarily by renal excretion might interact more significantly with high dosages of oral purines or with excessive amounts of inorganic phosphate. The effect that could conceivably be problematic would be a slowing, in response to an increase in intracellular urate or phosphate, etc., of the rate of biliary or renal excretion of a given drug. That's one reason it's always necessary to discuss these things with one's doctor.
Nonetheless, urate has been used to treat various forms of liver disease in animal models [one example: Garcia-Ruiz et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16941682)], and researchers have shown that urate can protect against mitochondrial dysfunction induced by a wide variety of treatments that produce mitochondrial dysfunction by increasing peroxynitrite formation (http://scholar.google.com/scholar?hl=en&q=mitochondrial+peroxynitrite+urate+OR+uric). A lot of factors and disease states can increase peroxynitrite formation, and the "antioxidant" or "nitrosative-degradation-by-proxy," more accurately, effects of urate, along with its apparent capacity to decrease or directly inhibit PARP-1 activity, make it more useful than many other compounds or antioxidants, in my opinion. As I've discussed in past postings, it may well be advantageous for an antioxidant, such as urate, to not be regenerated. Nonetheless, urate can, for example, regenerate melatonin and guanosine radical species by apparently-nonenzymatic mechanisms (http://scholar.google.com/scholar?hl=en&q=melatonin+regeneration+urate). And, as far as the rest of this posting is concerned, there's evidence that hypophosphatemia and intracellular phosphate depletion in the liver may contribute to liver damage in some cases and disease states (see past postings). One of the most important considerations in the context of phosphate homeostasis is to be aware that, in my opinion, the "phosphate" contained in inositol hexakisphosphate and other phytate compounds, in cereal grains and "plant proteins," etc., is unlikely to provide much, if any, utilizable phosphate in humans [see here: (http://hardcorephysiologyfun.blogspot.com/2009/08/phytates-as-potentially-poor-sources-of.html); (http://hardcorephysiologyfun.blogspot.com/2009/07/phytates-inositol-hexaphosphate-and.html)]. As far as my own calculation of my "dietary phosphate" intake went, I didn't even bother to include a contribution of cereal-grain phosphate. I put a big "NOTH-THING" by the spot on the page for the mg phosphate derived from phytate-containing foods. But I can't make that determination or calculation for anyone except myself. If I had been in the business of obtaining "hocus-pocus-microbial-phytase-derived-phantom-phosphate" phosphate from foods, maybe I'd have listed an actual number. But anyway, as with any compound, bizzarely-high dosages could cause problems. In response to massive dosages of either uricogenic purines or inorganic phosphate, those problems could take the form of interactions with other OAT substrates.
No comments:
Post a Comment