Abstract
The glycine deportation system is an essential component of glycine catabolism in man whereby 400 to 800 mg glycine per day are deported into urine as hippuric acid. The molecular escort for this deportation is benzoic acid, which derives from the diet and from gut microbiota metabolism of dietary precursors. Three components of this system, involving hepatic and renal metabolism, and renal active tubular secretion help regulate systemic and central nervous system levels of glycine. When glycine levels are pathologically high, as in congenital nonketotic hyperglycinemia, the glycine deportation system can be upregulated with pharmacological doses of benzoic acid to assist in normalization of glycine homeostasis. In congenital urea cycle enzymopathies, similar activation of the glycine deportation system with benzoic acid is useful for the excretion of excess nitrogen in the form of glycine. Drugs which can substitute for benzoic acid as substrates for the glycine deportation system have adverse reactions that may involve perturbations of glycine homeostasis. The cancer chemotherapeutic agent ifosfamide has an unacceptably high incidence of encephalopathy. This would appear to arise as a result of the production of toxic aldehyde metabolites which deplete ATP production and sequester NADH in the mitochondrial matrix, thereby inhibiting the glycine deportation system and causing de novo glycine synthesis by the glycine cleavage system. We hypothesize that this would result in hyperglycinemia and encephalopathy. This understanding may lead to novel prophylactic strategies for ifosfamide encephalopathy. Thus, the glycine deportation system plays multiple key roles in physiological and neurotoxicological processes involving glycine.
The glycine deportation system and its pharmacological consequences
The glycine deportation system is an essential component of glycine catabolism in man whereby 400 to 800 mg glycine per day are deported into urine as hippuric acid. The molecular escort for this deportation is benzoic acid, which derives from the diet ...
ncbi.nlm.nih.gov
4. Pharmacological consequences of the glycine deportation system
Salicylic acid (SA) is the active metabolite of the widely-used oral analgesic and anti-inflammatory drug aspirin (acetylsalicylic acid). Plant products containing SA have been used as remedies against pain and fever for at least 2500 years. Because salicylates are widely used and readily available as over-the-counter medications, they are often abused, with more than 10,000 toxic events per annum in the US (Pearlman & Gambhir, 2009). SA is conjugated with GLY forming salicylglycine, or salicyluric acid, which constitutes >70% urinary metabolites of SA or aspirin (Levy, 1965). This reaction was demonstrated to occur in bovine liver mitochondria and dependent upon CoA and ATP (Forman et al., 1971), analogous to the reaction used by the glycine deportation system (GDS) with benzoic acid (BA). A series of 2-substituted benzoic acids has been investigated in mouse liver and kidney mitochondria. The best substrate for both systems was BA itself, with activities of 25.1 and 69.3 nmol/mg for liver and kidney mitochondria, respectively (Kasuya et al., 2000). It was also reported that SA is not conjugated with glycine (GLY) by liver mitochondria, but by kidney mitochondria only. Purified medium-chain acyl-CoA synthetases from mouse and bovine liver mitochondria showed the highest activity with hexanoic, octanoic, and decanoic acids, metabolized BA, but neither enzyme metabolized SA (Kasuya et al., 2006). These were virtually identical findings to those reported in the original paper on the bovine liver mitochondrial enzyme over 50 years previously, in which SA was also found not to be a substrate for the hepatic enzyme (Schachter & Taggart, 1954). There is clearly a species difference in SA conjugation with GLY between the ox (Forman et al., 1971) and the mouse (Kasuya et al., 2000).
Regarding humans, as discussed above (Section 3.3.3), the GDS operates well in kidney, especially in the cortex (Pacifici et al., 1991). In the intact human subject, it is generally very difficult to recognize that a metabolic reaction occurs in the kidney. It has been suggested that a metabolite with low plasma levels and an unexpectedly high urinary concentration is probably being produced by the kidney (Vree et al., 1992). Clearly, kidney is a major site of SA conjugation with GLY, although there are expected to be species differences in this regard. An interesting observation that appears to confirm that BA and SA may not overlap completely in how they scavenge GLY was a report that BA had a pronounced effect on the formation of salicyluric acid from SA in man, but SA had no effect upon the formation of hippuric acid (HA) from BA. In addition, HA formation could be enhanced by GLY administration, but salicyluric acid formation was not influenced by the administration of GLY (Amsel& Levy, 1969).
A study of aspirin overdose revealed that plasma GLY concentrations ~6 to 9 h after overdosing were 9.4 ± 0.5 mg/1 (125 ± 7 µM) compared with 15.7±1.1 mg/1 (209±15µM) for healthy volunteers who had not taken aspirin. Healthy volunteers who took a single 500 mg tablet of aspirin had intermediate values of 12.8±0.5 mg/l (171 ±7 µM) (Patel et al., 1990). Aspirin administration, in particular aspirin overdose, causes GLY deportation, presumably via the renal mitochondrial system. It is of note that aspirin intoxication causes multiple CNS effects, including confusion, coma, seizures, dizziness, lethargy, delirium, stupor, incoordination, restlessness, hallucinations, cerebral edema, agitation, encephalopathy, and psychosis (Pearlman & Gambhir, 2009), many of which might be attributed to hypoglycinemia effecting lower brain GLY concentrations. Here, the GDS, by accepting SA, a simple substituted BA, may play a role in the pattern of life-threatening CNS pathologies in aspirin poisoning.
Regarding humans, as discussed above (Section 3.3.3), the GDS operates well in kidney, especially in the cortex (Pacifici et al., 1991). In the intact human subject, it is generally very difficult to recognize that a metabolic reaction occurs in the kidney. It has been suggested that a metabolite with low plasma levels and an unexpectedly high urinary concentration is probably being produced by the kidney (Vree et al., 1992). Clearly, kidney is a major site of SA conjugation with GLY, although there are expected to be species differences in this regard. An interesting observation that appears to confirm that BA and SA may not overlap completely in how they scavenge GLY was a report that BA had a pronounced effect on the formation of salicyluric acid from SA in man, but SA had no effect upon the formation of hippuric acid (HA) from BA. In addition, HA formation could be enhanced by GLY administration, but salicyluric acid formation was not influenced by the administration of GLY (Amsel& Levy, 1969).
A study of aspirin overdose revealed that plasma GLY concentrations ~6 to 9 h after overdosing were 9.4 ± 0.5 mg/1 (125 ± 7 µM) compared with 15.7±1.1 mg/1 (209±15µM) for healthy volunteers who had not taken aspirin. Healthy volunteers who took a single 500 mg tablet of aspirin had intermediate values of 12.8±0.5 mg/l (171 ±7 µM) (Patel et al., 1990). Aspirin administration, in particular aspirin overdose, causes GLY deportation, presumably via the renal mitochondrial system. It is of note that aspirin intoxication causes multiple CNS effects, including confusion, coma, seizures, dizziness, lethargy, delirium, stupor, incoordination, restlessness, hallucinations, cerebral edema, agitation, encephalopathy, and psychosis (Pearlman & Gambhir, 2009), many of which might be attributed to hypoglycinemia effecting lower brain GLY concentrations. Here, the GDS, by accepting SA, a simple substituted BA, may play a role in the pattern of life-threatening CNS pathologies in aspirin poisoning.
Nicotinic acid (NA), also known as niacin or vitamin B3 is an essential human nutrient, which, when absent, causes a disease called pellagra. The recommended dietary allowance of NA is 14 mg for adult females and 16 mg for adult males, or the equivalent amount of dietary tryptophan, from which NA can be synthesized (60 mg tryptophan yields 1 mg NA) (IOM, 1998). In 1955, it was discovered that large doses of NA lowered serum cholesterol concentrations, both in healthy volunteers given 4g and in “patients with various diseases” (not specified) given 1 g. These authors also observed that all their healthy medical student volunteers (n= 11) experienced flushing and burning sensations in the skin (Altschul et al., 1955). NA was also used in the 1950s for the treatment of migraine at a dose of 50 mg four times a day, above which flushing sometimes occurred (Nelson, 1955).
Several investigators studied the effects of NA on lipid metabolism in vitro in an attempt to discover the mechanism by which NA lowered serum cholesterol. By feeding NA in the diet to rats at 1, 2, 3, and 4%, after first generating fatty liver with a “special hypolipotropic diet” (not specified), dose-dependent reduction in hepatic cholesterol content was reported with NA. This author proposed that the low availability of CoA was the cause of depressed cholesterol synthesis (Schön, 1958). At the same time, Merrill, who studied the incorporation of sodium [1-14C]acetate into cholesterol in rat liver slices, pointed out that metabolic requirements for NA excretion might alter cholesterol biosynthesis (Merrill, 1958). It was then reported that incubation of rat liver slices with NA led to an increase in fatty acid biosynthesis at the expense of the synthesis of sterols (Hardy et al., 1960). Again, this would suggest a competition for CoA resources within mitochondria. Because NA is conjugated with glycine (GLY) (Ding et al., 1989) and therefore can be a molecular escort for GLY in the glycine deportation system (GDS), it is probable that the GDS utilizes extra CoA resources after the administration of large doses of NA. This may form the basis of these early theories of the mode of action of NA in lowering serum cholesterol by inhibiting its de novo synthesis in the liver. However, this may happen predominantly in the kidney and not the liver because administration of salicylic acid (SA) inhibits the conjugation of NA in the GDS in human volunteers (Ding et al., 1989).
It is recognized today that NA is a powerful lipid-altering drug that can lower levels of atherogenic apolipoprotein B-containing lipoproteins, such as LDL, VLDL, IDL, and Lp(a), while raising levels of atheroprotective HDL cholesterol. However, its use is limited by side-effects, especially flushing (incidence 25 to 40%), although gastrointestinal problems and metabolic effects may also present a problem (Creider et al., 2012). These authors also cite several studies that have reported that high-dose aspirin (325 mg) is the most effect means by which flushing could be prevented. This efficacy was not shared by ibuprofen, so it is unlikely that prevention of flushing is mediated by inhibition of prostaglandin synthesis, as various authors have suggested. Much more probable is an interaction between SA and NA at the level of the GDS, which is already known (Ding et al., 1989). In any case, the administration of aspirin will surely elevate plasma levels of NA and one must therefore propose that the flushing mechanism involves a metabolite of NA rather than NA itself. Nevertheless, ablation of the major limiting side-effect of this useful lipid-lowering drug certainly must contain a component of the GDS. Co-administration of NA and SA will elevate plasma GLY concentrations, and the role of GLY, either centrally or systemically, in the flushing response is completely unknown.
Several investigators studied the effects of NA on lipid metabolism in vitro in an attempt to discover the mechanism by which NA lowered serum cholesterol. By feeding NA in the diet to rats at 1, 2, 3, and 4%, after first generating fatty liver with a “special hypolipotropic diet” (not specified), dose-dependent reduction in hepatic cholesterol content was reported with NA. This author proposed that the low availability of CoA was the cause of depressed cholesterol synthesis (Schön, 1958). At the same time, Merrill, who studied the incorporation of sodium [1-14C]acetate into cholesterol in rat liver slices, pointed out that metabolic requirements for NA excretion might alter cholesterol biosynthesis (Merrill, 1958). It was then reported that incubation of rat liver slices with NA led to an increase in fatty acid biosynthesis at the expense of the synthesis of sterols (Hardy et al., 1960). Again, this would suggest a competition for CoA resources within mitochondria. Because NA is conjugated with glycine (GLY) (Ding et al., 1989) and therefore can be a molecular escort for GLY in the glycine deportation system (GDS), it is probable that the GDS utilizes extra CoA resources after the administration of large doses of NA. This may form the basis of these early theories of the mode of action of NA in lowering serum cholesterol by inhibiting its de novo synthesis in the liver. However, this may happen predominantly in the kidney and not the liver because administration of salicylic acid (SA) inhibits the conjugation of NA in the GDS in human volunteers (Ding et al., 1989).
It is recognized today that NA is a powerful lipid-altering drug that can lower levels of atherogenic apolipoprotein B-containing lipoproteins, such as LDL, VLDL, IDL, and Lp(a), while raising levels of atheroprotective HDL cholesterol. However, its use is limited by side-effects, especially flushing (incidence 25 to 40%), although gastrointestinal problems and metabolic effects may also present a problem (Creider et al., 2012). These authors also cite several studies that have reported that high-dose aspirin (325 mg) is the most effect means by which flushing could be prevented. This efficacy was not shared by ibuprofen, so it is unlikely that prevention of flushing is mediated by inhibition of prostaglandin synthesis, as various authors have suggested. Much more probable is an interaction between SA and NA at the level of the GDS, which is already known (Ding et al., 1989). In any case, the administration of aspirin will surely elevate plasma levels of NA and one must therefore propose that the flushing mechanism involves a metabolite of NA rather than NA itself. Nevertheless, ablation of the major limiting side-effect of this useful lipid-lowering drug certainly must contain a component of the GDS. Co-administration of NA and SA will elevate plasma GLY concentrations, and the role of GLY, either centrally or systemically, in the flushing response is completely unknown.
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