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 1161<br />
TABLE 2. Mutagenicity of selected amino-imidazo-azaarene food mutagens in the Ames test in the presence of S-9<br />
mix toward the frameshift-sensitive Salmonella typhimurium strains TA98 <strong>and</strong> TA1538, <strong>and</strong> toward the base<br />
substitution-sensitive strain TA100<br />
Systematic Name Abbreviation<br />
man diet (12). On the other h<strong>and</strong>, based on a dietary<br />
survey of the United States population, the combined<br />
daily intake of PhIP, 8-MeIQx, 4,8-DiMeIQx, <strong>and</strong> IQ was<br />
estimated to be only 1.4 �g for a 70-kg person (540).<br />
A large body of evidence indicates that Cr <strong>and</strong>/or Crn<br />
are important precursors of AIA mutagens. 1) In different<br />
fried bovine tissues as well as in meat extracts, beef<br />
flavors, bouillons, <strong>and</strong> gravies, mutagenicity correlated<br />
with the Cr <strong>and</strong>/or Crn content of the sample (for references,<br />
see Refs. 534, 807, 902). Fried meat, heart, <strong>and</strong><br />
tongue contain high levels of Cr <strong>and</strong> Crn <strong>and</strong> displayed<br />
considerable mutagenicity. Liver <strong>and</strong> kidney, on the other<br />
h<strong>and</strong>, have only low levels of Cr <strong>and</strong> Crn <strong>and</strong> yielded no<br />
significant mutagenicity upon frying. Likewise, the mutagenicity<br />
of plant foods is at least 10-fold lower compared<br />
with animal (muscle) foods, which may be due to the<br />
absence of Cr <strong>and</strong> Crn in plants (934).<br />
2) Addition of Cr or PCr to meat samples or to beef<br />
extracts before the cooking process increased mutagenicity<br />
up to 40-fold <strong>and</strong> AIA contents up to 9-fold (see Refs.<br />
423, 481, 744, 902). Conversely, treatment of beef meat<br />
with creatinase before frying reduced the Cr content <strong>and</strong><br />
the mutagenicity by 65 <strong>and</strong> 73%, respectively (1066). 3)<br />
Addition of Cr before cooking of meat had no influence on<br />
the number or on the relative proportions of AIA mutagens<br />
formed, but increased the level of all mutagens<br />
approximately to the same extent (see Ref. 744). This<br />
implies that Cr or Crn may be involved in the formation of<br />
Mutagen. TA1538,<br />
rev/�g Mutagen. TA98, rev/�g<br />
Mutagen. TA100,<br />
rev/�g<br />
2-Amino-3-methylimidazo[4,5-f]quinoline IQ (1) 200,000–400,000 94,000–898,000 3,150–12,100<br />
2-Amino-3,4-dimethylimidazo[4,5-f]quinoline MeIQ (1) 700,000–1,017,000 253,000–47,000,000 24,500–182,000<br />
2-Amino-3-methylimidazo[4,5-f]quinoxaline IQx (2) 100,000–105,000 17,800–75,000 1,500<br />
2-Amino-3,4-dimethylimidazo[4,5-f]quinoxaline 4-MeIQx (2) 875,000–1,208,000 1,162,000 51,000<br />
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline 8-MeIQx (2) 70,000–99,300 35,700–417,000 1,500–14,000<br />
2-Amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline 4,8-DiMeIQx (2) 130,000–320,000 126,000–435,000 8,000–11,200<br />
2-Amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline 7,8-DiMeIQx (2) 189,000 163,000–192,000 8,100–9,900<br />
2-Amino-4-hydroxymethyl-3,8-dimethylimidazo[4,5- 4-CH2OH-8-MeIQx (2) 99,000 2,600<br />
f]quinoxaline<br />
2-Amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline 7,9-DiMeIgQx (3) 670<br />
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine PhIP (4) 1,800–4,000 1,700–3,520 0–140<br />
2-Amino-1-methyl-6-(4-hydroxyphenyl)imidazo[4,5-b]pyridine 4�-OH-PhIP (4) 1.75 0<br />
2-Amino-1,6-dimethylimidazopyridine 1,6-DMIP (5) 8.0<br />
2-Amino-n,n,n-trimethylimidazopyridine TMIP (6) 100,000<br />
2-Amino-(1 or 3),6-dimethylfuro[2,3-e]imidazo[4,5-b]pyridine (7) �10,000<br />
Naphthyridine mutagen (8) �80,000<br />
2,6-Diamino-3,4-dimethyl-7-oxopyrano[4,3-g]benzimidazole (9) 7,000 5,200 550<br />
4-Amino-1,6-dimethyl-2-methylamino-1H,6H-pyrrolo[3,4- Cre-P-1 (10) 19,000 400<br />
f]benzimidazole-5,7-dione<br />
2-Amino-5-ethylidene-1-methylimidazol-4-one AEMI (11)<br />
2-Amino-1-methyl-5-propylideneimidazol-4-one AMPI (12)<br />
Numbers in parentheses refer to the compound number shown in Figure 15. For references, see Refs. 119, 170, 215, 236; see also Refs. 237,<br />
239, 417, 440, 481, 493, 494, 521, 710, 907, 937, 994, 1065. rev, Revertants.<br />
all AIA food mutagens. 4) The latter conclusion is supported<br />
by the fact that all currently known AIA food<br />
mutagens (Fig. 15, structures 1–8) share a 2-aminoimidazo<br />
moiety that resembles strikingly the structure of<br />
Crn. 5) Most AIA mutagens could be generated artificially<br />
in simple model systems containing Cr or Crn, amino<br />
acids, <strong>and</strong> sugars (see below). Omission of Cr <strong>and</strong> Crn<br />
from these model systems greatly reduced mutagenicity<br />
(e.g., Refs. 721, 904). 6) Finally, heating of model mixtures<br />
containing Phe <strong>and</strong> isotopically labeled Cr revealed that<br />
the 1-nitrogen, the methyl-carbon, <strong>and</strong> the amino-nitrogen<br />
from Cr all are incorporated into PhIP (236).<br />
As an apparent exception to the rule, AIA mutagens<br />
(IQ, MeIQ, PhIP) have been detected in beer, wine,<br />
roasted coffee beans, <strong>and</strong> cigarette smoke as well as in<br />
urine of smokers of black tobacco, despite the absence of<br />
Cr <strong>and</strong> Crn in yeasts <strong>and</strong> plants (see Refs. 215, 424, 592).<br />
An amusing interpretation of these findings has been provided<br />
by Jägerstad et al. (424): “A possible explanation<br />
could be that animal urine, containing creatin(in)e, has<br />
been spread over the leaves of the tobacco plant through<br />
fertilization.” As a more plausible alternative, other guanidines<br />
may participate in AIA formation (see below).<br />
Artificial model systems have widely been used to<br />
study both the probable precursors <strong>and</strong> the reaction pathways<br />
leading to the formation of AIA mutagens. In these<br />
model systems, Cr or Crn was mixed with a variety of<br />
substances <strong>and</strong> incubated for different periods of time at