Creatine

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For the use of creatine to increase athletic performance, see Creatine supplements.
Not to be confused with creatinine.
Creatine
Skeletal formula of creatine
Ball and stick model of creatine
Identifiers
CAS number 57-00-1 YesY
PubChem 586
ChemSpider 566 YesY
UNII MU72812GK0 YesY
EC number 200-306-6
DrugBank DB00148
KEGG C00300 YesY
MeSH Creatine
ChEBI CHEBI:16919 N
ChEMBL CHEMBL283800 YesY
RTECS number MB7706000
ATC code C01EB06
Beilstein Reference 907175
Gmelin Reference 240513
3DMet B00084
Jmol-3D images Image 1
Image 2
Properties
Molecular formula C4H9N3O2
Molar mass 131.13 g mol−1
Appearance White crystals
Odor Odourless
Melting point 255 °C (491 °F; 528 K)
Solubility in water 13.3 g L−1 (at 18 °C)
log P −1.258
Acidity (pKa) 3.429
Basicity (pKb) 10.568
Isoelectric point 8.47
Thermochemistry
Specific
heat capacity
C
171.1 J K−1 mol−1 (at 23.2 °C)
Std molar
entropy
So298
189.5 J K−1 mol−1
Std enthalpy of
formation
ΔfHo298
−538.06–−536.30 kJ mol−1
Std enthalpy of
combustion
ΔcHo298
−2.3239–−2.3223 MJ mol−1
Pharmacology
Elimination
half-life
3 hours
Hazards
GHS pictograms The exclamation-mark pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
GHS signal word WARNING
GHS hazard statements H315, H319, H335
GHS precautionary statements P261, P305+351+338
EU classification Irritant Xi
R-phrases R36/37/38
S-phrases S26, S36
Related compounds
Related alkanoic acids
Related compounds Dimethylacetamide
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Creatine (/ˈkrətn/ or /ˈkrətɪn/[1][2]) is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of adenosine triphosphate (ATP). Creatine was identified in 1832 when Michel Eugène Chevreul isolated it from the basified water-extract of skeletal muscle. He later named the crystallized precipitate after the Greek word for meat, κρέας (kreas). Early analysis showed that human blood is approximately 1% creatine, and the highest concentrations are found in animal blood, brain (0.14%), muscle (0.50%), and testes (0.18%). The liver and kidney contain approximately 0.01% creatine. Today, creatine content (as a percentage of crude protein) can be used as an indicator of meat quality.[3]

In solution, creatine is in equilibrium with creatinine.[4]

Creatine is a derivative of the guanidinium cation.

Biosynthesis

Creatine is naturally produced in the human body from amino acids primarily in the kidney and liver. It is transported in the blood for use by muscles. Approximately 95% of the human body's total creatine is located in skeletal muscle.[5]

Creatine is not an essential nutrient, as it is manufactured in the human body from L-arginine, glycine, and L-methionine.[6]

In humans and animals, approximately half of stored creatine originates from food (about 1 g/day, mainly from meat).[6] A study involving 18 vegetarians and 24 non-vegetarians on the effect of creatine in vegetarians showed that total creatine was significantly lower than in non-vegetarians. Since vegetables are not the primary source of creatine, vegetarians can be expected to show lower levels of directly derived muscle creatine. However, the subjects happened to show the same levels after using supplements.[7] Given the fact that creatine can be synthesized from the above-mentioned amino acids, protein sources rich in these amino acids can be expected to provide adequate capability of native biosynthesis in the human body.[6]

The enzyme L-arginine:glycine amidinotransferase (AGAT) is a mitochondrial enzyme responsible for catalyzing the first rate-limiting step of creatine biosynthesis, and is primarily expressed in the kidneys and pancreas.[8]

The second enzyme in the pathway (GAMT, Guanidinoacetate N-methyltransferase, EC:2.1.1.2) is primarily expressed in the liver and pancreas.[8]

Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[9] Clinically, there are three distinct disorders of creatine metabolism. Deficiencies of the two synthetic enzymes can cause L-arginine:glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect is caused by mutations in SLC6A8 and inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.[10]

The phosphocreatine system

Creatine, synthesized in the liver and kidney, is transported through the blood and taken up by tissues with high energy demands, such as the brain and skeletal muscle, through an active transport system. The concentration of ATP in skeletal muscle is usually 2-5 mM, which would result in a muscle contraction of only a few seconds.[11] Fortunately, during times of increased energy demands, the phosphagen (or ATP/PCr) system rapidly resynthesizes ATP from ADP with the use of phosphocreatine (PCr) through a reversible reaction with the enzyme creatine kinase (CK). In skeletal muscle, PCr concentrations may reach 20-35 mM or more. Additionally, in most muscles, the ATP regeneration capacity of CK is very high and is therefore not a limiting factor. Although the cellular concentrations of ATP are small, changes are difficult to detect because ATP is continuously and efficiently replenished from the large pools of PCr and CK.[11] Creatine has the ability to increase muscle stores of PCr, potentially increasing the muscle’s ability to resynthesize ATP from ADP to meet increased energy demands.[12] For a review of the creatine kinase system and the pleiotropic actions of creatine and creatine supplementation see.[13]

The pathway for the synthesis of creatine
Arg - Arginine; GATM - Glycine amidinotransferase; GAMT - Guanidinoacetate N-methyltransferase; Gly - Glycine; Met - Methionine; SAH - S-adenosyl homocysteine; SAM - S-adenosyl methionine.
The color scheme is as follows:enzymes, coenzymes and the Met part, substrate names, the Gly part, the Arg part

Health effects

Supplements

Main article: Creatine supplements

Creatine supplements are used by athletes, bodybuilders, wrestlers, sprinters, and others who wish to gain muscle mass. The Mayo Clinic states that creatine has been associated with asthmatic symptoms and warns against consumption by persons with known allergies to creatine.[14]

A 2009 systematic review discredited concerns that creatine supplementation could affect hydration status and heat tolerance and lead to muscle cramping and diarrhea.[15][16]

There are reports of kidney damage with creatine use, such as interstitial nephritis; patients with kidney disease should avoid use of this supplement.[14] In similar manner, liver function may be altered, and caution is advised in those with underlying liver disease, although studies have shown little or no adverse impact on kidney or liver function from oral creatine supplementation.[17] In 2004 the European Food Safety Authority (EFSA) published a record which stated that oral long-term intake of 3g pure creatine per day is risk-free.[18] The reports of damage to the kidneys by creatine supplementation have been scientifically refuted.[19][20]

Long-term administration of large quantities of creatine is reported to increase the production of formaldehyde, which has the potential to cause serious unwanted side effects. However, this risk is largely theoretical because urinary excretion of formaldehyde, even under heavy creatine supplementation, does not exceed normal limits.[21][22]

Extensive research has shown that oral creatine supplementation at a rate of five to 20 grams per day appears to be very safe and largely devoid of adverse side-effects,[23] while at the same time effectively improving the physiological response to resistance exercise, increasing the maximal force production of muscles in both men and women.[24][25]

A meta analysis found that creatine treatment resulted in no abnormal renal, hepatic, cardiac, or muscle function.[26]

While some research indicates that supplementation with pure creatine is safe, a survey of 33 commercially available supplements found that over 50% of them exceeded the European Food Safety Authority recommendations in at least one contaminant. The most prevalent of these contaminants was creatinine, a breakdown product of creatine also produced by the body.[27] Creatinine was present in higher concentrations than the European Food Safety Authority recommendations in 44% of the samples. About 15% of the samples had detectable levels of dihydro-1,3,5-triazine or a high dicyandiamide concentration. Heavy metals contamination was not found to be a concern, with only minor levels of mercury being detectable.

Pharmacokinetics

Endogenous serum or plasma creatine concentrations in healthy adults are normally in a range of 2–12 mg/L. A single 5 g (5000 mg) oral dose in healthy adults results in a peak plasma creatine level of approximately 120 mg/L at 1–2 hours post-ingestion. Creatine has a fairly short elimination half-life, averaging just less than 3 hours, so to maintain an elevated plasma level it would be necessary to take small oral doses every 3–6 hours throughout the day. After the "loading dose" period (1–2 weeks, 12-24 g a day), it is no longer necessary to maintain a consistently high serum level of creatine. As with most supplements, each person has their own genetic "preset" amount of creatine they can hold. The rest is eliminated as waste. A typical post-loading dose is 2-5 g daily.[28][29][30]

Pregnancy and breastfeeding

There is a lack of scientific information on the effects of creatine supplementation during pregnancy and breastfeeding.[citation needed] As of 2014 it is not clear if taking creatine during pregnancy affects the rate of cerebral palsy or other neurological problems.[31]

Pasteurized cow's milk contains higher levels of creatine than human milk.[32][33]

Muscle disorders

A meta analysis found that creatine treatment increased muscle strength in muscular dystrophies, and potentially improved functional performance.[34] It has also been implicated in decreasing mutagenesis in DNA[35]

Improved cognitive ability

A placebo-controlled double-blind experiment found that a group of subjects composed of vegetarians and vegans who took 5 grams of creatine per day for six weeks showed a significant improvement on two separate tests of fluid intelligence, Raven's Progressive Matrices, and the backward digit span test from the WAIS. The treatment group was able to repeat longer sequences of numbers from memory and had higher overall IQ scores than the control group. The researchers concluded that "supplementation with creatine significantly increased intelligence compared with placebo."[36] A subsequent study found that creatine supplements improved cognitive ability in the elderly.[37] A study on young adults (0.03 g/kg/day for six weeks, e.g., 2 g/day for a 70-kilogram (150 lb) individual) failed to find any improvements.[38]

See also

References

  1. ^ Entry "creatine" in Merriam-Webster Online Dictionary.
  2. ^ Wells, J. C. (2000). Longman Pronunciation Dictionary. Harlow, England: Pearson Education Ltd.
  3. ^ http://pubs.acs.org/doi/abs/10.1021/jf60128a026?journalCode=jafcau
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  5. ^ "Creatine". MedLine Plus Supplements. U.S. National Library of Medicine. 20 July 2010. Retrieved 2010-08-16. 
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  8. ^ a b "ETH ETH E-Collection: Methylglyoxal, creatine and mitochondrial micro-compartments - ETH E-Collection". E-collection.ethbib.ethz.ch. 19 April 2008. doi:10.3929/ethz-a-004636659 (inactive 2014-10-11). Retrieved 2010-08-16. 
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  13. ^ doi:10.1007/s00726-011-0877-3.
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  18. ^ http://www.efsa.europa.eu/EFSA/efsa_locale-1178620753824_1178620761727.htm
  19. ^ doi:10.1007/s00421-007-0669-3.
  20. ^ doi:10.1023/A:1022469320296.
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  30. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 366-368.
  31. ^ Dickinson, H; Bain, E; Wilkinson, D; Middleton, P; Crowther, CA; Walker, DW (19 December 2014). "Creatine for women in pregnancy for neuroprotection of the fetus.". The Cochrane database of systematic reviews 12: CD010846. PMID 25523279. 
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  33. ^ Wallimann, Theo; Tokarska-Schlattner, Malgorzata; Schlattner, Uwe (1 May 2011). "The creatine kinase system and pleiotropic effects of creatine". Amino Acids (Springer Wien) 40 (5): 1271–1296. doi:10.1007/s00726-011-0877-3. ISSN 0939-4451. PMC 3080659. PMID 21448658. 
  34. ^ Kley, R. A.; Tarnopolsky, M. A.; Vorgerd, M. (2011). Kley, Rudolf A, ed. "Cochrane Database of Systematic Reviews". Cochrane database of systematic reviews (Online) (2): CD004760. doi:10.1002/14651858.CD004760.pub3. PMID 21328269.  |chapter= ignored (help) edit
  35. ^ Rahimi, R. (2011). "Creatine Supplementation Decreases Oxidative DNA Damage and Lipid Peroxidation Induced by a Single Bout of Resistance Exercise". Journal of Strength and Conditioning Research 25 (12): 3448–3455. doi:10.1519/JSC.0b013e3182162f2b. PMID 22080314.  edit
  36. ^ Rae C, Digney AL, McEwan SR, Bates TC; Digney; McEwan; Bates (October 2003). "Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial". Proceedings. Biological Sciences / the Royal Society 270 (1529): 2147–50. doi:10.1098/rspb.2003.2492. PMC 1691485. PMID 14561278. 
  37. ^ McMorris T, Mielcarz G, Harris RC, Swain JP, Howard A; Mielcarz; Harris; Swain; Howard (September 2007). "Creatine supplementation and cognitive performance in elderly individuals". Neuropsychology, Development, and Cognition. Section B, Aging, Neuropsychology and Cognition 14 (5): 517–28. doi:10.1080/13825580600788100. PMID 17828627. 
  38. ^ Rawson ES, Lieberman HR, Walsh TM, Zuber SM, Harhart JM, Matthews TC; Lieberman; Walsh; Zuber; Harhart; Matthews (September 2008). "Creatine supplementation does not improve cognitive function in young adults". Physiology & Behavior 95 (1–2): 130–4. doi:10.1016/j.physbeh.2008.05.009. PMID 18579168. 

External links