Biological and chemical studies on 8,9-dihydroxy-8,9-dihydro-aflatoxin B1 and some of its esters. 1980

B F Coles, and A M Welch, and P J Hertzog, and S J Lindsay, and R C Garner
Department of Chemistry, University of York, Heslington, York Y01 5DD, UK.

A number of aflatoxin B1 (AFB1) derivatives have been synthesized including 8-acyloxy- and 8-benzoyloxy-9-hydroxy-8,9-dihydro-AFB1 compounds, AFB1-8,9-diol and [3H] AFB1 labelled at the 9 position. AFB1-hydroxyesters appear to be models of AFB1-8,9-oxide in that they are bacterial mutagens, stimulate unscheduled DNA synthesis in HeLa cells and react with DNA to give trans-8,9-dihydro-8(7-guanyl)-9-hydroxy-AFB1 as the major adduct after hydrolysis. The potency of the hydroxyesters increases with ease of release of the ester grouping at position 8. Absence of the hydroxyl at position 9 gives compounds which are readily hydrolysed in water but are not biologically active. The hydroxyesters hydrolyse in water to give AFB1-diol, providing a convenient means of synthesis of this compound. Studies with AFB1-diol show that it reacts with one molecule of Tris base, probably through the ring-opened furan form, with the amino group of the Tris. Acidification results in ring closure in an analogous manner to AFB1-diol. AFB1-diol binds to DNA in vitro as well as to liver slice DNA. The compound is mutagenic towards S. typhimurium TA100 without metabolic activation. The implications of these findings are discussed in relation to the mechanisms of AFB1 carcinogenicity.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008297 Male Males
D008862 Microsomes, Liver Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough. Liver Microsomes,Liver Microsome,Microsome, Liver
D009152 Mutagenicity Tests Tests of chemical substances and physical agents for mutagenic potential. They include microbial, insect, mammalian cell, and whole animal tests. Genetic Toxicity Tests,Genotoxicity Tests,Mutagen Screening,Tests, Genetic Toxicity,Toxicity Tests, Genetic,Genetic Toxicity Test,Genotoxicity Test,Mutagen Screenings,Mutagenicity Test,Screening, Mutagen,Screenings, Mutagen,Test, Genotoxicity,Tests, Genotoxicity,Toxicity Test, Genetic
D009153 Mutagens Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. Clastogen,Clastogens,Genotoxin,Genotoxins,Mutagen
D009682 Magnetic Resonance Spectroscopy Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING). In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D002851 Chromatography, High Pressure Liquid Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed. Chromatography, High Performance Liquid,Chromatography, High Speed Liquid,Chromatography, Liquid, High Pressure,HPLC,High Performance Liquid Chromatography,High-Performance Liquid Chromatography,UPLC,Ultra Performance Liquid Chromatography,Chromatography, High-Performance Liquid,High-Performance Liquid Chromatographies,Liquid Chromatography, High-Performance
D004247 DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA, Double-Stranded,Deoxyribonucleic Acid,ds-DNA,DNA, Double Stranded,Double-Stranded DNA,ds DNA
D004249 DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a MUTATION or a block of DNA REPLICATION. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (PYRIMIDINE DIMERS) or interstrand crosslinking. Damage can often be repaired (DNA REPAIR). If the damage is extensive, it can induce APOPTOSIS. DNA Injury,DNA Lesion,DNA Lesions,Genotoxic Stress,Stress, Genotoxic,Injury, DNA,DNA Injuries
D004952 Esters Compounds derived from organic or inorganic acids in which at least one hydroxyl group is replaced by an –O-alkyl or another organic group. They can be represented by the structure formula RCOOR’ and are usually formed by the reaction between an acid and an alcohol with elimination of water. Ester

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