Creatine and Creatinine Metabolism - Physiological Reviews

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1166 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80 561). The contribution of O-acetylation, O-sulfonylation, O-prolylation, and O-phosphorylation to metabolic activation differs considerably between individual N-OH-AIA, tissues, and species, but all four reactions seem to be relevant (161). Genotoxicity of PhIP, in contrast to IQ, does not depend on acetyltransferase activity in Chinese hamster ovary cells, which is in line with the finding that O-sulfonylation of N-OH-PhIP is quantitatively more important than O-acetylation in the production of DNA adducts (see Refs. 235, 1121). With some exceptions (see Ref. 872), a satisfactory correlation is observed for a given tissue between the capacity to metabolically activate AIA, the extent of AIA- DNA adduct formation, and the frequency of AIA-induced tumor development. For IQ, MeIQ, and 8-MeIQx, the principal site of metabolic activation is the liver. Accordingly, liver displays the highest level of DNA adducts, and tumors of the liver develop with high frequency in animals treated with these AIA. Metabolic activation of PhIP also occurs primarily in the liver, but most probably due to efficient detoxification (see above), only low levels of PhIP-DNA adducts are formed in this tissue. Consistent with this finding, PhIP induces liver tumors in neither mice nor rats. In the mammary gland of Fischer 344 (F344) rats, DNA adduct formation of N-OH-PhIP was �3and 17-fold higher than with N-OH-IQ and N-OH-8-MeIQx, respectively (159). Correspondingly, PhIP induced mammary carcinomas in F344 rats, whereas IQ and 8-MeIQx did not. Compared with rat and human, cynomolgus monkeys have a similar capacity to metabolically activate IQ. On the other hand, metabolic activation of 8-MeIQx and PhIP is considerably lower (212, 235). In line with this observation, IQ, MeIQ, and 8-MeIQx are potent carcinogens in mice and rats, whereas in cynomolgus monkeys, 8-MeIQx and PhIP induced no tumors so far. Of particular interest with regard to human health perspectives is the question of the human cancer risk due to food-borne AIA. Although previous estimations arrived at maximum risks of up to 1 in 1,000 (see Ref. 215), a more recent calculation, based on an extensive literature review on the levels of AIA in cooked foods and on mean food consumption figures in the United States, yielded an incremental cancer risk due to AIA of �10 �4 (540; see also Ref. 289). For several reasons, this number is still subject to considerable uncertainty. 1) The cancer risk was extrapolated from carcinogenicity data obtained in rats. However, due to differences in metabolic activation and detoxification pathways, human tissues may be more susceptible to AIA than rodent tissues (see, e.g., Ref. 235). 2) Because of (genetic) polymorphisms of AIA-activating enzymes, in particular of cytochrome P-4501A2 and NAT2 (see Ref. 235), some subjects may be considerably more susceptible to AIA than others. Accordingly, subjects with a phenotype of high cytochrome P-4501A2 and/or NAT2 activities have an increased risk of developing colorectal cancer of potentially up to 1 in 50. 3) Chronic exposure to low levels of AIA may be more harmful than expected. As a matter of fact, combined treatment of rats with 5 or 10 mutagenic heterocyclic amines may result in synergistic rather than additive enhancement of mutagenic and carcinogenic effects (see Refs. 342, 344). Similarly, MeIQ was shown to enhance the mutagenicity of the drinking water mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)furanone (1090). 4) There are still only limited data available on the food levels of AIA. Only very recently, for example, PhIP levels in pan-fried, broiled, or grilled chicken were found to be much higher than previously suspected (896). 4. Nitrosation products of Cr and Crn as potential human carcinogens An alternative pathway resulting in the formation of mutagenic and carcinogenic principles may be nitrosation of Cr, Crn, or methylguanidine (MG). Nitrate is reduced to nitrite by oral bacteria, and favorable conditions for nitrosation prevail in the stomach. A strong positive correlation was observed between the dietary nitrate (and nitrite) intake and gastric cancer mortality (340, 649). In the United States, a fourfold reduction in the calculated gastric nitrite load between 1925 and 1981 was associated with a threefold decrease in gastric cancer mortality. Nitrosation of Cr, Crn, and MG has been studied mostly in in vitro systems. Crn is converted to N-methyl- N-nitrosourea (MNU) in four successive steps, three of which involve reaction with nitrite (651). MNU may also be formed from MG, with methylnitrosoguanidine and methylnitrosocyanamide as intermediates (see Ref. 649). MG, in turn, may be of dietary origin or, alternatively, may be formed in vivo, either from Crn via the reaction sequence proposed to proceed in uremic patients when serum [Crn] is increased (see sect. IXH) or by an oxidation reaction of Cr or Crn catalyzed by iron or copper salts. Nitrosation of Cr successively yields sarcosine and Nnitrososarcosine (155). The latter, finally, may be dehydrated to N-nitrosodimethylamine. Of the nitrosation products shown in Figure 17, Crn-5-oxime and 1-methylhydantoin-5-oxime were not mutagenic in the Ames test (651). Crn-5-oxime also displayed no carcinogenic activity (1113). MNU is a potent mutagen and direct-acting carcinogen, producing tumors in several species and in a variety of organs, particularly in stomach and CNS, but also in intestine, kidney, and skin (541, 987, 1088). In line with the observation that O 6 -methylguanine is the reaction product of MNU with DNA, MNU mostly induced base substitutions from GC to AT (see Ref. 1160). Compared with MNU, methylnitrosocyanamide displayed even higher mutagenicity in the Ames test, and it was there-
July 2000 CREATINE AND CREATININE METABOLISM 1167 fore concluded that the active principle responsible for the mutagenicity of nitrosated MG is mainly methylnitrosocyanamide (223, 224). However, methylnitrosocyanamide is only moderately carcinogenic. N-nitrososarcosine is weakly carcinogenic in both rats and mice, causing esophageal and liver cell carcinomas, respectively (1113). N-nitrosodimethylamine is a highly toxic carcinogen and was suggested to be formed in the small intestine of uremic patients (550; see also Ref. 537). Even though these findings might be taken to indicate that nitrosation products of Cr, Crn, and MG represent a significant health hazard, a series of arguments point to the contrary. 1) When nitrosation was studied under real and simulated gastric juice conditions, only MG yielded significant mutagenicity in the Ames test, whereas Cr, PCr, Crn, or guanidinoacetate gave no or very low mutagenicity (224). However, MG ingestion is likely to be �100-fold lower than that of Cr and Crn (650). 2) Reaction of Crn with 0.4 M nitrite for1hatpH1gave only a 0.0003% yield of MNU (see Ref. 651). This must be compared with a nitrite level of 54 �M in gastric juice of subjects from an area with a high gastric cancer incidence (see Ref. 650). 3) Nitrite participates in three steps in the reaction sequences from Crn to MNU and from Cr to N-nitrososarcosine. Given the low nitrite level of �54 �M, it is highly unlikely that these reactions proceed to a significant extent. 5. Conclusions Circumstantial evidence suggests that Cr and Crn may add to human carcinogenesis by forming either AIA or nitroso compounds that covalently modify guanine bases and thereby result in DNA mutations. On the basis of current knowledge, however, Cr- and Crn-derived AIA and nitroso compounds may impose only a minor health risk. Nevertheless, because the formation and modes of action of these substances are still only incompletely understood, intensive research on this topic must continue. In the meantime, consumption of vitamin C, chlorophylls, or other dietary supplements, or a change in cooking habits, seem to be feasible ways to reduce the FIG. 17. Potential nitrosation products of Cr, Crn, and methylguanidine (MG). MNU, methylnitrosourea; MU, methylurea. Nitrosation products that were shown to be carcinogenic in animal experiments are boxed. potential health risk even further. Vitamin C was shown to inhibit nitrosation reactions by reducing nitrite to NO (see Ref. 649), and lactic acid bacteria, antioxidants, flavonoids, chlorophylls, food-coloring agents, isothiocyanates, and capsaicin reduce mutagenicity and carcinogenicity due to AIA mutagens (see, e.g., Refs. 20, 153, 235, 328, 363, 416, 465, 546, 589, 845, 872, 990, 1095, 1140). G. Creatin(in)e Metabolism and Brain Function Total CK activity and Cr content are lower in brain than in skeletal muscle or heart. Even though it might be concluded that, therefore, the CK system plays a less prominent role in brain physiology, there is ample evidence for close correlations between Cr metabolism and CK function on one hand and proper brain function on the other hand. In chicken and rat brain, the B-CK, M-CK, and Mi-CK isoforms were localized specifically to cell types for which high and fluctuating energy demands can be inferred (e.g., cerebellar Bergmann glial cells, Purkinje neurons, and glomerular structures) (450, 1081). Substantial evidence supports a direct coupling of CK (or ArgK) with growth cone migration (1087), with Na � -K � -ATPase and neurotransmitter release, as well as an involvement of CK in the maintenance of membrane potentials, calcium homeostasis, and restoration of ion gradients before and after depolarization (1081). CK and Cr were also suggested to participate in inhibition of mitochondrial permeability transition (64, 717), which is thought to be linked to both apoptotic and necrotic neuronal cell death. Although the situation may be somewhat different in the rat and piglet brain (375, 1102), the PCr and total Cr concentrations as well as the flux through the CK reaction are significantly higher in gray than in white matter of the human brain (105, 573, 594, 784, 1086). These findings parallel the higher rate of ATP turnover in cerebral gray compared with white matter. Furthermore, electroencephalogram (EEG) activity increases considerably in the first 2–3 wk of life in the rat. Large increases in the response of rat cortical slice respiration to electrical stimulation, hyperthermia, or increased extracellular [KCl]
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