Bilirubin and Related Tetrapyrroles Inhibit Food-Borne Mutagenesis: A Mechanism for Antigenotoxic Action against a Model Epoxide

Mölzer, Christine; Huber, Hanspeter; Steyrer, Andrea; Ziesel, Gesa V.; Wallner, Marlies; Hong, Hung T.; Blanchfield, Joanne T.; Bulmer, Andrew Cameron; Wagner, Karl‐Heinz

doi:10.1021/np4005807

Cited by 14 publications

(19 citation statements)

References 59 publications

(126 reference statements)

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“…Although the inhibitory effects of BPs (5.8, 5.9, 5.10) on environmental mutagens (5.1, 5.4) has been reported in a variety of studies, 14,17,19,35,186 the inhibition mechanism has not been explored. Therefore, the investigation of possible chemical reactions between activated mutagens and BPs is a focus of our study to elucidate the mechanism of this inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17][18][19][20][21] High concentrations of 1.1 (UCB) in the blood and bodily tissues leads to serious health problems such as jaundice, athetoid cerebral palsy, and hearing loss or deafness, particularly in newborn infants where the blood-brain barrier is not yet well formed and so may allow bilirubin to enter the brain. 3,15 The beneficial biological effects of BPs and their derivatives have been of mounting interest recently as their potent anti-mutagenicity, 15,18,19,21 and anti-oxidant properties 18,[22][23][24][25][26][27][28] come to light as well as their ability to bind to certain important enzymes. [29][30][31] The chemical details and their potential physiology properties will be reviewed in the following section.…”

Section: The Biological Properties Of Bile Pigments and Their Derivatmentioning

confidence: 99%

“…One such theory is that there are significant non-covalent attractive forces between the polyaromatic mutagens and the -systems of the BPs resulting in aggregation. Although this is a popular hypothesis, 2,15,19,21 very few reports present evidence that these physical interactions contribute to the activity. 21 The presence of a saturated methylene group at the C10-bridge of 1.1 (UCB) blocks conjugation between the two halves of the molecule.…”

Section: Physical Interactions Between Mutagens and Bile Pigmentsmentioning

confidence: 99%

“…145,152 Non-covalent interactions were also considered to be an important contribution for inhibitory action of bile pigments (BPs) to mutagens in biological systems. 15,19,21 The most common experimental methods that are applied to study physical interactions between solvent as a result of these interactions. X-ray crystallography also showed evidence of CH- interactions in phenylalanine derivatives with a distance of only 2.6 Å from Ho to the ring centroid.…”

Section: Determining Physical Interactions Between Mutagens and Bile mentioning

confidence: 99%

“…These properties have been exploited in nanomaterials comprising metal and BF 2 complexes of dipyrrolylmethenes (BODIPY) 177 which generate a strongly polarised -electron system, and have proved useful as optical limiters, 178 sensors, fluorescent markers, 179,180 photosensitisers, 181,182 antioxidants, 183 and laser radiation limiters. 184,185 Other important pyrrole containing compounds, for example, bile pigments and their dimethyl esters, are also reported in many reviews of their potential biological properties, such as antioxidant [18][19][20]183 and anti-mutagenic acivities 15,18,19,186 . In spite of these promising properties and a variety of syntheses which aim to optimise the yield and efficiency, the need of pyrroles and dipyrroles for chemical interaction studies is not commercially available.…”

Section: Caco-2 Cell Culturementioning

confidence: 99%

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Physical and chemical interactions between bile pigments and polyaromatic mutagens

Trieu¹

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A major cause of cancer in humans is exposure to mutagenic compounds. This raises the question of how humans can be protected from these environmental mutagens. Bile pigments (BPs) such as biliverdin, unconjugated bilirubin and protoporphyrin and their derivatives have recently been found to act as antioxidants and inhibit the mutagenic effects of several known environmental mutagens including 2-aminofluorene, benzo [α]pyrene, and 2-amino-1-methyl-6-phenylimido [4,5-b]pyridine. Despite these promising results, very little is known about the mechanisms by which this inhibition is achieved. Understanding these mechanisms would be useful for future drug development. Therefore, this PhD thesis aims to explore physical and chemical interactions between BPs and mutagens. Effects of BPs on the bioavailability and metabolism of mutagens were also examined in vitro using the colorectal adenocarcinoma (Caco-2 cell) monolayer model and the human liver S9 fraction.The physical interactions between mutagens and BPs were examined using three different methods:NMR, UV and effects of bioavailability. The results of the comparison of the NMR spectra of mutagens in the absence and presence of BPs showed very little changes in the chemical shifts of the protons and the changes that did occur were the result of acid/base interactions between the BPs and mutagens. The UV spectrum of each mutagen was measured in the presence and absence of varying concentrations of BPs, and there were no changes to the UV spectra of any of the compounds. Strong physical interactions or aggregation of compounds can also affect their absorption across cell monolayers and so the apparent permeability of mutagens across Caco-2 cell monolayers in the presence and absence of BPs were measured. The results indicated that BPs increased the permeability of the mutagens slightly and effected how much of the compounds remained in tight association with the monolayer but the effects were small. These experiments provided evidence to suggest that physical interactions and aggregations are unlikely to be a major contributing mechanism of the inhibitory effects of BPs on environmental mutagens.Chemical reactions between BPs and the DNA modifying metabolites of mutagens (epoxides) were studied using styrene epoxide as a model for the reactive metabolites. Styrene epoxide is commercially available, stable and less toxic than the reactive metabolites of the mutagens.Competitive reactions were performed in which BPs and their derivatives were placed in solution with guanine and allowed to react with styrene epoxide. These reactions showed that BPs and their dimethyl esters are more reactive to the epoxide than guanine. Bile pigments primarily react through their carboxylic acid groups with the mono-and di-styrene epoxide esters being the major products isolated form the reactions. The pyrrole rings in bilirubin also showed some evidence of iii reaction with styrene epoxide though the products were too unstable to isolate. Thus, it was clear that BPs can effecti...

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