Creatine and Creatinine Metabolism - Physiological Reviews

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1162 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 temperatures of 37–250°C, either dry, in aqueous solution, or in diethylene glycol-water mixtures which display increased boiling points of 128–150°C. With the individual components varied, almost all AIA food mutagens could be generated in model systems, namely, IQ, MeIQ, IQx, 8-MeIQx, 4,8-DiMeIQx, 7,8-DiMeIQx, 7,9-DiMeIgQx, PhIP, and TMIP (for reviews and references, see Refs. 119, 236, 417, 424, 434, 492, 544, 710, 902). Similar to the situation in cooked foods, a variety of factors influence mutagen yield in model systems, e.g., temperature, incubation time, concentration of antioxidants as well as the nature, concentration, and proportion of the precursors (for reviews and references, see Refs. 417, 424, 434, 465, 902). Maximal mutagen yield was achieved by mixing Cr or Crn with an amino acid and a sugar in a molar ratio of 1:1:0.5. Remarkably, almost the same ratio between these components is found in bovine muscle (534). In most instances, omission of any one component from the ternary mixture greatly reduced mutagenicity. Crn proved to be a more potent precursor than Cr. Because, in addition, conversion of Cr to Crn is favored at elevated temperatures, Crn rather than Cr is likely to be the actual precursor of AIA mutagens. The amino acid in the ternary mixture determines not only the yield, but also the nature of the AIA mutagens produced. In mixtures with Cr(n) and glucose, Cys and Thr yield highest mutagenicity, followed by Lys, Ala, Ser, and Gly. In most of these ternary mixtures, 8-MeIQx and 4,8-DiMeIQx were identified as products. On the other hand, PhIP was only found in ternary mixtures containing Phe, Leu, Ile, or Tyr. The influence of sugars on mutagen production is somewhat more complex. In most but not all mixtures of Cr(n) and amino acids, addition of a variety of sugars (glucose, fructose, sucrose, lactose) increased mutagen formation. Fructose proved to be more potent than glucose, and sucrose was more potent than lactose. As mentioned above, maximal mutagenicity was reached at a molar ratio of Cr(n), amino acid, and sugar of 1:1:0.5. When the sugar concentration was further increased, progressive inhibition of mutagen formation occurred. This inhibition was suggested to be due either to Maillard reactions that are expected to become more prominent at elevated sugar concentrations, or to inhibition of the conversion of Cr to Crn by sugars. Model systems also produced new mutagens that have not been detected so far in cooked foods (for references, see Refs. 215, 905). From a heated mixture of Cr, Glu, and glucose, the AIA mutagen 2,6-diamino-3,4-dimethyl-7-oxo-pyrano[4,3-g]benzimidazole was isolated (Fig. 15, structure 9). The imidazo-quinoxaline 4,7,8-Tri- MeIQx was identified in a heated mixture of Ala, Thr, Crn, and glucose. Finally, pyrolysis of Cr monohydrate at 250– 400°C gave rise to the mutagenic compound Cre-P-1 (Fig. 15, structure 10). On the basis of the experiments with model systems, two alternative reaction pathways were proposed for the formation of imidazo-quinoline and imidazo-quinoxaline mutagens (for a detailed discussion, see Ref. 424). According to the first hypothesis, a pyridine or pyrazine and an aldehyde, both postulated to be formed from amino acids and sugars through Maillard reactions and Strecker degradations, react with Crn to yield an imidazo-quino(xa)line compound. In support of this hypothesis, IQ has recently been isolated, although in low yield, from a heated mixture of 2-methylpyridine, Crn, and acetylformaldehyde (544). According to the second hypothesis, Crn first undergoes an aldol condensation with an aldehyde to yield an intermediary creatinine-aldehyde which, subsequently, combines with a pyridine or pyrazine to give an imidazo-quino(xa)line compound. This hypothesis is supported by the identification of the postulated creatininealdehyde intermediates AEMI and AMPI (Fig. 15, structures 11 and 12) in heated mixtures of Crn and Thr, and by the generation of AEMI through direct reaction of Crn with acetaldehyde. Common to both hypotheses are the postulates that pyridines or pyrazines are obligatory intermediates and that these pyridines or pyrazines are formed from sugars and amino acids through Maillard reactions (see also Ref. 465). The validity of these assumptions is, however, questioned by several lines of evidence: 1) imidazo-quino(xa)lines were formed in binary systems lacking sugars, namely, in mixtures of Cr(n) with Pro, Phe, Ser, Ala, or Tyr. 2) In mixtures of Cr with Pro or Ser, addition of glucose did not stimulate mutagen formation. 3) Upon addition of a variety of pyridines or pyrazines to model systems, the amount of mutagenicity at most doubled or did not increase at all. 4) Finally, in cooked meat, a poor correlation was observed between mutagenicity and the level of Maillard reaction products (see Ref. 534). On the other hand, in model systems containing Crn, Thr, and radioactively labeled glucose, label was in fact incorporated into 8-MeIQx and 4,8-DiMeIQx (see Ref. 902). Taken together, these results imply that different reaction pathways have to be considered and that sugars may be involved in but are not essential for the formation of imidazo-quino(xa)lines. PhIP was identified in binary mixtures of Cr plus Phe, Crn plus Phe, and Cr plus Leu (see Refs. 424, 902, 989). When mixtures of Crn and Phe were dry-heated at 200°C, addition of glucose in a half-molar amount decreased rather than increased PhIP yield (989). Experiments with isotopically labeled Phe revealed that the whole phenyl ring, the 3-carbon atom, and the amino nitrogen of Phe are incorporated into PhIP (236). In the light of these findings, it comes as a surprise that in aqueous solution at pH 7.4 and at a temperature of 60°C, PhIP was only detected when sugars or aldehydes were added to mixtures of Crn plus Phe (591). It remains to be determined whether,
July 2000 CREATINE AND CREATININE METABOLISM 1163 depending on the temperature or on other parameters, different reaction pathways must also be considered for the formation of PhIP. Only a few studies have addressed the question of whether Cr(n) may be substituted by other guanidines in the formation of AIA mutagens. In binary mixtures with amino acids or ribose as well as in ternary mixtures with Gly and glucose, other guanidines (Arg, N G -methyl-L-arginine, 1-methylguanidine, aminoguanidine, and guanidine) yielded at least eightfold lower mutagenicity than Cr (491, 613, 721). In ternary mixtures with Phe and glucose, however, 1-methylguanidine gave rise to even higher mutagenicity than Cr. Unfortunately, nothing is known so far about the nature of the mutagens formed in these model systems. Patients with chronic renal failure are subject to an increased cancer risk. As is discussed in section IXH, the serum concentration of Crn is drastically increased in these patients, thereby creating “favorable” conditions for the formation of AIA. In fact, 8-MeIQx was detected in the dialysis fluid of all uremic patients examined (1134). The notion that this 8-MeIQx does not originate from meat consumption, but from de novo synthesis, is supported by the formation of AIA in a model system at as low a temperature as 37°C (591). The actual rate of in vivo AIA synthesis in uremic patients as well as its contribution to cancer development remain to be established. In conclusion, the studies on cooked foods and on model systems provide valuable information on the structure and on potential precursors of AIA mutagens. On the other hand, we still await a breakthrough in the understanding of the reactions involved in the formation of the individual classes of AIA mutagens. This knowledge, in turn, may help to define new strategies for reducing this potential health risk. 2. Mutagenicity and carcinogenicity of AIA For routine purposes, mutagenicity of AIA compounds is normally measured with the Ames test, using primarily the Salmonella typhimurium strains TA98, TA1538, and TA100. As can be seen in Table 2, AIA compounds are in general more mutagenic toward TA98 and TA1538, which are sensitive to frameshift mutations, than toward TA100, a strain that is sensitive to base substitutions. The high specific mutagenicities toward TA98 rank the AIA compounds among the most mutagenic substances currently known. For comparison, the carcinogens aflatoxin B1 and benzo[a]pyrene display specific mutagenicities of only 320–28,000 revertants/�g inS. typhimurium strains TA98 and TA100 (see Refs. 119, 215). In the Ames test, AIA compounds are not mutagenic as such but depend on metabolic activation by a rat liver S9 (9,000-g supernatant) fraction that contains activating enzymes that are not present in S. typhimurium (see below). The mutagenic potency of AIA compounds was corroborated in Drosophila as well as in a series of mammalian cell types such as Chinese hamster ovary and lung cells, mouse small intestinal stem cells, or mouse fibroblasts (see Refs. 119, 178, 215, 236, 794, 872). AIA compounds proved to stimulate DNA repair, measured as unscheduled DNA synthesis, as well as chromosomal damage, such as sister chromatid exchange and chromosomal aberrations. Furthermore, AIA induced preneoplastic lesions, e.g., foci positive for placental glutathione S-transferase (GST) and an increase in �-glutamyl transpeptidase activity in rat liver, or aberrant crypt foci in the colon of rodents (see Refs. 215, 320, 343, 514, 731). In all these nonmicrobial systems, the mutagenic activity of AIA compounds was, in general, much lower than in the Ames test. In Chinese hamster lung cells, for example, IQ, MeIQ, and 8-MeIQx were even less mutagenic than benzo[a]pyrene. Whereas in S. typhimurium, PhIP is the least mutagenic AIA (Table 2), it usually displayed higher mutagenicity than other AIA in mammalian cell types. This is noteworthy since in many cooked foods, PhIP is the most abundant AIA. The relationships between chemical structure and mutagenic activity were studied for a series of IQ analogs (see Refs. 178, 348, 907). Mutagenicity critically depends on the 2-amino group as well as on a methyl group either at the 1- or 3-position of the aminoimidazo ring. When a methyl group was attached to the 1-position (isoIQ), even higher mutagenicity was observed toward both TA98 and TA100 than when it was attached to the 3-position (IQ). Substitution of the 2-amino group with one or two methyl groups progressively decreased mutagenicity toward TA98 but increased (one methyl group) or only slightly decreased (two methyl groups) mutagenicity toward TA100. Mutagenicity also decreased greatly when the nitrogen atom in the quinoline part of the molecule was replaced by a carbon atom. IQ, MeIQ, 8-MeIQx, and PhIP were shown to be carcinogenic, although, so far, only at concentrations much higher than those normally observed in cooked foods (see Refs. 215, 289, 413, 523, 723, 794, 797, 872, 886, 920, 1000, 1001, 1096). In mice, tumors were induced in liver, lung, forestomach, and hematopoietic system. In rats, tumors were observed in liver, Zymbal gland, skin, small and large intestine, clitoral gland, mammary gland, and in the oral cavity. Finally, in cynomolgus monkeys, only IQ was carcinogenic and induced metastasizing hepatocellular carcinomas. Apart from apparent species differences in the carcinogenic effects of AIA compounds, considerable differences were also observed between individual AIA. Although the liver is one of the main targets of IQ, MeIQ, and 8-MeIQx in both rats and mice, PhIP only induced colon, mammary, and prostate carcinomas in rats and
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