Creatine and Creatinine Metabolism - Physiological Reviews

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-