Creatine and Creatinine Metabolism - Physiological Reviews

1160 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80
nificant analgesic action. Some distant Cr analogs were
also reported to have anti-inflammatory, analgesic, antihypertensive,
local anesthetic, and platelet antiaggregating
activities (78).
F. Significance of Cr and Creatinine for the
Formation of Food Mutagens and Carcinogens
1. Cr and Crn as probable precursors of the cooked
food mutagens and carcinogens of the aminoimidazo-azaarene
class
The processing of foods, and in particular the frying and
broiling of meat, is associated with the generation of mutagenic
and carcinogenic principles. A whole class of new
mutagens, the amino-imidazo-azaarenes (AIA), has been isolated
over the past 20 years from cooked foods. Sources of
AIA mutagens were broiled or fried fish, cooked chicken,
beef and pork meat, beef extracts, beef flavors, fried eggs, as
well as fumes from cooking meat (for reviews and references,
see Refs. 119, 178, 215, 235–238, 296, 495, 540, 807,
902, 1009). The dietary origin of the AIA mutagens is supported
by the fact that they are detected in the urine of
healthy volunteers eating normal diet, but not of inpatients
receiving parenteral alimentation (1031). According to their
chemical structures, the currently known AIA mutagens can
be classified into five groups, namely, the imidazo-quinolines
(IQ and MeIQ; Fig. 15, structure 1; for systematic names, see
Table 2), the imidazo-quinoxalines (IQx, 4-MeIQx, 8-MeIQx,
4,8-DiMeIQx, 7,8-DiMeIQx, 4-CH2OH-8-MeIQx, and 7,9-
DiMeIgQx; Fig. 15, structures 2 and 3), the imidazo-pyridines
(PhIP, 4�-OH-PhIP, DMIP, and TMIP; Fig. 15, structures
4–6), the oxygen-containing AIA (Fig. 15, structure 7),
and the naphthyridines (Fig. 15, structure 8).
The amount of mutagenicity and of AIA compounds
formed during the cooking of meat depends on a number
of factors, for example, on the cooking method, time, and
temperature as well as on the proportions of fat, sugars,
dietary fibers, and amino acids in the meat sample (see
Refs. 119, 743, 807, 902, 903, 919, 1009). The generation of
AIA can be minimized, e.g., by microwave pretreatment of
meat, marinades, addition of soy protein, chlorophylls or
antioxidants before cooking, or by using oil rather than
butter for frying (see Refs. 119, 153, 435, 436, 465, 743,
839). Among the AIA compounds, IQ, 8-MeIQx, 4,8-
DiMeIQx, and PhIP are the most important mutagens and
together contribute �80% of the mutagenicity (see Ref.
238). In terms of actual mass, the concentrations of IQ,
MeIQ, 8-MeIQx, 4,8-DiMeIQx, and PhIP were determined
in a series of cooked foods (beef, chicken, hamburger,
beef extracts, sun-dried sardines, and fish) to be between
zero and 158, 72, 300, 28, and 480 ng � (g cooked food) �1 ,
respectively, whereby at least some of the upper limits
represent overestimations due to methodological artifacts
(for reviews and references, see Refs. 215, 235, 238, 495,
FIG. 15. Food mutagens derived most likely from Cr or Crn. 1)
Imidazoquinolines (IQ): R 1 � H 3 IQ; R 1 � CH 3 3 MeIQ; 2 and 3)
imidazoquinoxalines (IQx): 2)R 1 � R 2 � R 3 � H 3 IQx; R 1 � CH 3,R 2 �
R 3 � H 3 4-MeIQx; R 1 � R 3 � H, R 2 � CH 3 3 8-MeIQx; R 1 � R 2 � CH 3,
R 3 � H 3 4,8-DiMeIQx; R 1 � H, R 2 � R 3 � CH 3 3 7,8-DiMeIQx; R 1 �
CH 2OH, R 2 � CH 3,R 3 � H 3 4-CH 2OH-8-MeIQx; 3) 7,9-DiMeIgQx; 4-6)
imidazopyridines (IP): 4) R 1 � H 3 PhIP; R 1 � OH 3 4�-OH-PhIP; 5)
1,6-DMIP; 6) TMIP; 7) 2-amino-(1 or 3),6-dimethylfuro[2,3-e]imidazo-
[4,5-b]pyridine; 8) naphthyridine mutagen; 9-12) mutagens detected so
far only in model systems containing Cr or Crn: 9) 2,6-diamino-3,4dimethyl-7-oxo-pyrano[4,3-g]benzimidazole;
10) Cre-P-1; 11) AEMI; 12)
AMPI. For further details, see text; for references, see Refs. 215, 235,
237.
540, 896, 902, 903, 956). On the basis of the mean consumption
figures in the Netherlands, it has been estimated
that 15–20 �g of AIA are consumed per kilogram of hu-