The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis an...

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Creatine and Creatinine Metabolism

In order to study the mutagenic effects of heterocyclic aromatic amines (HAAs) in cells of human origin, five compounds, namely 2-amino-3-methyl-imidazo[4,5-f]quinoline (IQ), 2-amino-3, 4-dimethyl-imidazo[4,5-f]quinoline (MeIQ), 2-amino-3, 8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), the pyridoimidazo derivative 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), were tested in micronucleus (MN) assays with a human derived hepatoma (HepG2) cell line. All HAAs caused significant, dose-dependent effects. The activities of IQ, MeIQ, MeIQx and PhIP were similar (lowest effective concentrations 25-50 microM), whereas Trp-P-1 was effective at a dose of >/=2.1 microM. In addition, the HAAs were tested in MN assays with Chinese hamster ovary (CHO) cells and in Salmonella strain YG1024 using HepG2 cell homogenates as an activation mix. In the CHO experiments, positive results were obtained with Trp-P-1 and PhIP, whereas the other compounds were devoid of activity under all experimental conditions. The discrepancy in the responsivity of the two cell lines is probably due to differences in their acetylation capacity: enzyme measurements with 2-aminofluorene as a substrate revealed that the cytosolic acetyltransferase activity in the HepG2 cells is approximately 40-fold higher than that of the CHO cells. In the bacterial assays all five HAAs gave positive results but the ranking order was completely different from that seen in the HepG2/MN experiments (IQ > MeIQ > Trp-P-1 >/= MeIQx >> PhIP) and the mutagenic potencies of the various compounds varied over several orders of magnitude. The order obtained in bacterial tests with rat liver S9 mix was more or less identical to that seen in the tests with HepG2 cell homogenates but the concentrations of the amines required to give positive results were in general substantially lower (10(-5)-10(-1) microM). Overall, the results of the present study indicate that MN/HepG2 tests might reflect the mutagenic effects of HAAs more adequately than other in vitro mammalian cell systems due to the presence of enzymes involved in the metabolic conversion of the amines.

Genotoxic effects of heterocyclic aromatic amines in human derived hepatoma (HepG2) cells

This review surveys the chemical and biological factors that are correlated with the mutagenic activity of the aromatic and heterocyclic amines. Particular attention is given to the predicted quantum chemical properties of the parent amines and their metabolites. A number of chemical properties have been found to correlate well with measured mutagenic potency, including log P, the energies of the frontier orbitals of the parent amines, and the thermodynamic stability of the nitrenium ion, possibly the ultimate DNA-binding species. These correlations are intriguing clues to the mutagenic activity of the aromatic amines; however, many factors still await final explanation, including the exact mechanisms of the metabolic enzymes, the identity(s) of the ultimate DNA-binding species, the reaction mechanism in the DNA-adduction, the role of sequence context in the covalent and non-covalent binding of the adducts, and the role of DNA repair.

Chemical and biological factors affecting mutagen potency.

A set of 16 mutagenic aminoimidazo-azaarenes, including four that have been isolated from cooked foods and identified as bacterial mutagens and rodent carcinogens, was selected from a larger series previously published [Hatch et al. (1991): Environ Mol Mutagen 17:4–19] for an in-depth structure-activity study using computational methods. Structural features believed to affect mutagenic potency were tabulated. Molecular orbital energies and other electronic properties of these compounds were calculated using Huckel, semiempirical AM1, and ab initio quantum mechanical methods. Factor interrelationships were studied by multiple linear regression and canonical correlation analyses. Our goal was an improved understanding of the chemical basis of mutagenicity for this class of heterocyclic amines. The major findings were as follows: 1) mutagenic potency is related to the size of the aromatic ring system; 2) potency is enhanced by the presence and location of an N-methyl group; 3) potency is enhanced by addition of ring nitrogen atoms in pyridine, quinoline, and quinoxaline configurations; 4) potency is inversely related to the energy of the LUMO (lowest unoccupied molecular orbital) of the parent amines; 5) potency is directly, though weakly, related to the LUMO energy of the derived nitrenium ions; and 6) the calculated thermodynamic stability of the nitrenium ions (relative to the parent amine) is directly correlated with nitrenium LUMO energy and with the negative charge on the exocyclic nitrogen atom. Although this study raises several intriguing issues relating mutagenicity to chemical properties, further study will be required to determine the plausibility of the nitrenium ion as the ultimate mutagen for binding to DNA. © 1996 Wiley-Liss, Inc.

Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes.

Heterocyclic Aromatic Amines

We tested four isomeric imidazonaphthyridines and one imidazoquinoline compound for mutagenic activity in the Ames/Salmonella mutagenicity assay, using strain TA98 and strain YG1024, an analogue of strain TA98 with elevated O-acetyltransferase levels. Their potency was related to calculated electronic parameters. Five compounds with a linear arrangement of 3 rings showed a positive response in strain YG1024. Compound 2 (1-methylimidazo[4,5-b][1,7]naphthyridin-2-amine) is the most mutagenic in both strains, giving specific activities of about 200 and 30 revertants per microgram in strains YG1024 and TA98, respectively. Three of the compounds were weak mutagens, giving a positive dose-response only in strain YG1024, with 3-5 revertants per microgram. A higher response of all five compounds in strain YG1024 as opposed to TA98 indicates that they require O-acetyltransferase activity for their metabolism. Mutagenic potencies in strain YG1024 were positively correlated to the energy of the LUMO (lowest unoccupied molecular orbital) of the nitrenium ion.

Structure-mutagenicity relationships of four amino-imidazonaphthyridines and imidazoquinolines.

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Structure-mutagenicity relationships of four amino-imidazonaphthyridines and imidazoquinolines.