Creatine and Creatinine Metabolism - Physiological Reviews

1164 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80
lymphomas in (adult) mice. Potential reasons for these
discrepancies may be species- and tissue-specific differences
in expression and/or substrate specificity of the
mutagen-activating enzymes.
In neonatal mice, three single doses of AIA (IQ,
8-MeIQx, or PhIP) given on days 1, 8, and 15 after birth
induced liver tumors in high incidence within 8–12 mo
(192). This is remarkable for three reasons: 1) the total
AIA dose administered to these neonatal mice was 5,000to
10,000-fold lower than AIA doses used in long-term
carcinogenicity assays on adult rodents. 2) AIA are accumulated
in mammary gland and milk of lactating rats and
are also found in liver and blood of suckling pups as well
as in the eye and liver of fetal mice (see Refs. 413, 618).
These results suggest that the health risk imposed by AIA
is more pronounced in neonates than in adults and that
the detoxification mechanisms may not yet be fully developed
soon after birth. 3) Metabolic activation of 8-MeIQx
by hepatic microsomal fractions was undetectable in 6- to
11-day-old rats, then increased with age and reached a
maximum in weanling animals (804). This latter finding
raises questions about the mechanism of action of AIA in
neonates (see below).
Limited data have been published on the activation of
oncogenes in AIA-induced tumors (for reviews and references,
see Refs. 587, 588, 682, 1013). In only one of five rat
hepatocellular carcinomas induced by IQ, the H-ras-1 and
a second unidentified oncogene (neither ras nor neu)
were activated (410). In the case of rat colon tumors, nine
carcinomas and two adenomas induced by IQ and nine
carcinomas induced by PhIP displayed mutations neither
in the p53 gene nor in the Ki-ras, Ha-ras,orN-ras families.
A high incidence of Ha-ras, Ki-ras, and p53 gene mutations
was, however, observed in rat Zymbal gland and
mouse forestomach tumors induced by IQ, MeIQ, and
8-MeIQx. Ki-ras mutations were detected in 4 of 37 aberrant
crypt foci induced by IQ in the rat colon. In four of
eight PhIP-induced rat colon tumors investigated, a total
of five mutations in the APC gene were detected. All five
mutations involved deletion of a guanine base in a 5�-
GGGA-3� sequence. On the other hand, APC mutations
were seen in only 2 of 13 IQ-induced rat colon tumors and
involved C-to-T and T-to-C base substitutions. Finally, 7 of
8 colon tumors and 9 of 15 mammary gland tumors induced
by PhIP had microsatellite alterations in at least
one locus, whereas no microsatellite mutations were observed
in IQ-induced colon tumors.
In addition to their mutagenic and carcinogenic effects,
PhIP and IQ induced cardiac damage in rats and
nonhuman primates, respectively (see Refs. 872, 1001). In
addition, IQ, MeIQ, 8-MeIQx, 4,8-DiMeIQx, and 7,8-
DiMeIQx were reported to inhibit monoamine oxidase
(MAO)-A and MAO-B with K i values of 140–250 and 240–
450 �M, respectively (604).
3. Metabolic activation and detoxification pathways
of AIA and their impact on estimated AIA-derived
cancer risks
As already mentioned, AIA are not mutagenic as
such, but must be metabolically activated by a series of
enzymes to exert their mutagenic effects (Fig. 16). The
FIG. 16. Metabolism of amino-imidazo-azaarenes (AIA). The aminoimidazo part of the AIA is drawn correctly,
whereas the remaining parts of the molecule are represented schematically by a ring. Reactions involved in the activation
of AIA are drawn from left to right. Inactivation reactions, on the other hand, are arranged vertically. R 1 is OCOCH 3 for
acetylation, OSO 3 � for sulfonylation, O-prolyl for prolylation, and OPO3 2� for phosphorylation.