Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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July 2000 CREATINE AND CREATININE METABOLISM 1139<br />
side reactions (biodegradation), <strong>and</strong> the extent of feedback<br />
repression of AGAT exerted by the Cr analog.<br />
To get a feeling for the potencies of the Cr analogs<br />
that have been used so far, the available knowledge will<br />
shortly be summarized (Table 1). The Cr analogs <strong>and</strong><br />
corresponding synthetic phosphagens cover a wide range<br />
of potencies to act as substrates for CK. cCr <strong>and</strong> PcCr are<br />
rather good substrates, both in vitro <strong>and</strong> in vivo (810). On<br />
the other h<strong>and</strong>, GPA <strong>and</strong> PGPA, with 1,000- to 1,500-fold<br />
decreased V max/K m values, are expected to be poor CK<br />
substrates. Nevertheless, upon changes in workload in<br />
the perfused myocardium of control <strong>and</strong> GPA-treated<br />
rats, [PCr] <strong>and</strong> [PGPA], respectively, displayed very similar<br />
changes, both as far as the absolute concentration<br />
changes <strong>and</strong> the kinetics of the alterations are concerned<br />
(135). This finding points to an “overcapacity” of the CK<br />
system <strong>and</strong> suggests that under normal in vivo conditions<br />
as well as under most experimental regimens, PGPA is a<br />
satisfactory substitute of PCr. Therefore, conclusions as<br />
to the function of PCr in organs of animals fed these<br />
analogs may be misleading. hcCr <strong>and</strong> especially PhcCr are<br />
extremely poor substrates of CK. As a matter of fact,<br />
PhcCr is very slowly consumed under in vivo conditions<br />
(810). 3-Guanidinobutyrate is not phosphorylated at all in<br />
vivo (1163). Even though, on first sight, hcCr <strong>and</strong> 3-guanidinobutyrate<br />
seem to be perfectly suited for investigations<br />
of the physiological functions of the CK/PCr/Cr system,<br />
they both suffer the limitations to be accumulated<br />
rather inefficiently by the tissues <strong>and</strong> to replace PCr <strong>and</strong><br />
Cr only incompletely (810, 1163). These may be the reasons<br />
for GPA being the most widely used Cr analog in<br />
physiological experiments.<br />
When porcine carotid arteries, containing almost no<br />
Mi-CK, were superfused with either GPA, methyl-GPA<br />
(mGPA), guanidinoacetic acid (GAA), or cCr, all of these<br />
Cr analogs entered the tissue <strong>and</strong> became phosphorylated<br />
(74). When, subsequently, oxidative metabolism was inhibited<br />
by cyanide, PCr, PGPA, PGAA, <strong>and</strong> PmGPA were<br />
consumed over a similar time course, despite different<br />
kinetic properties of these analogs in vitro. PcCr, on the<br />
other h<strong>and</strong>, was utilized at a significantly lower rate.<br />
Nevertheless, the results show that these Cr analogs may<br />
all serve as substrates for cytosolic CK. In contrast, only<br />
Cr <strong>and</strong> cCr stimulated respiration in isolated rat heart<br />
mitochondria, whereas GAA, mGPA, <strong>and</strong> GPA were ineffective<br />
(74, 130, 1163; see also Ref. 1044). These findings<br />
may indicate that Mi-CK displays narrower substrate<br />
specificity than the cytosolic CK isoenzymes or, more<br />
unlikely, that the outer mitochondrial membrane is impermeable<br />
to GAA, mGPA, <strong>and</strong> GPA.<br />
Compared with CK, the Cr transporter seems to be<br />
considerably less specific toward Cr analogs (Table 1).<br />
This conclusion has recently been corroborated by experiments<br />
on the cloned Cr transporters from Torpedo, rabbit,<br />
<strong>and</strong> human (see also sect. VIIC) (318, 319, 691, 840,<br />
927). In cells transiently transfected with Cr transporter<br />
cDNA, nonlabeled Cr <strong>and</strong> GPA inhibit the uptake of radioactive<br />
Cr very efficiently <strong>and</strong> to approximately the<br />
same extent. 4-Guanidinobutyrate, guanidinoacetate, <strong>and</strong><br />
2-amino-3-guanidinopropionate are somewhat less inhibitory,<br />
while Crn has only little effect. In experiments on the<br />
repression of AGAT activity in embryonic <strong>and</strong> developing<br />
chicken liver, Cr, cCr, N-ethylguanidinoacetate, <strong>and</strong> Nacetimidoylsarcosine<br />
proved to be powerful repressors,<br />
whereas N-acetimidoylglycine, 1-carboxymethyl-2iminohexahydropyrimidine,<br />
N-propylguanidinoacetate,<br />
<strong>and</strong> N-methyl-3-guanidinopropionate caused either no or<br />
just a small reduction in AGAT activity (809, 1078).<br />
To conclude, an ideal Cr analog unfortunately does<br />
not exist. Therefore, experiments with Cr analogs have to<br />
be analyzed <strong>and</strong> interpreted with caution. Definite conclusions<br />
should only be based on a detailed comparison of<br />
several analogs with different kinetic <strong>and</strong> thermodynamic<br />
properties <strong>and</strong>/or on a variety of experimental approaches:<br />
ultrastructural, physiological, <strong>and</strong> biochemical.<br />
B. Cr Analog Administration as a Means<br />
of Studying CK Function: Facts <strong>and</strong><br />
Potential Pitfalls<br />
Cr analogs have been used frequently for studying the<br />
relevance of the CK system for cellular energetics in<br />
various tissues. Most of these studies have been performed<br />
on skeletal muscle where Cr analog (in particular,<br />
GPA) administration caused a series of functional<br />
changes (for a review see Ref. 1125). For example, GPA or<br />
3-guanidinobutyrate (GBA) administration decreases developed<br />
muscle tension as well as the rates of tension<br />
development <strong>and</strong> relaxation (556, 636, 637, 656, 890, 1044,<br />
1073, 1074), suppresses posttetanic twitch potentiation<br />
<strong>and</strong> the staircase phenomenon (see Refs. 636, 637), improves<br />
endurance performance (556, 637, 983, 1044, 1073,<br />
1074), <strong>and</strong> causes ultrastructural abnormalities (535) (see<br />
also below). Even though these results have been taken to<br />
indicate that the CK system is important for proper muscle<br />
function, some authors arrived at opposite conclusions<br />
by finding either no or only minor changes in muscle<br />
mechanics upon GPA feeding (889). Either way, results<br />
<strong>and</strong> conclusions on CK function based on Cr analogfeeding<br />
experiments must be interpreted with caution,<br />
since these compounds may have a series of confounding<br />
side effects.<br />
GPA is a physiological constituent of mammalian<br />
blood plasma, erythrocytes, brain, liver, kidney, aorta,<br />
<strong>and</strong> urine, <strong>and</strong> its concentration is considerably increased<br />
in uremic patients (see, e.g., Refs. 163, 181, 321, 554, 555,<br />
597, 628, 998, 1132). GPA may be formed by AGAT<br />
through transamidination between Arg <strong>and</strong> �-alanine<br />
(1089) (see also sects. VIIA <strong>and</strong> IXH). It may thus be