title: Biological and chemical studies on 8,9-dihydroxy-8,9-dihydro-aflatoxin B1 and some of its esters.
abstract: 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.
authors.affiliation: Department of Chemistry, University of York, Heslington, York Y01 5DD, UK.
authors.forename: B F
authors.initials: BF
authors.lastname: Coles
authors.forename: A M
authors.initials: AM
authors.lastname: Welch
authors.forename: P J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: S J
authors.initials: SJ
authors.lastname: Lindsay
authors.forename: R C
authors.initials: RC
authors.lastname: Garner
mesh_terms: D016604:Aflatoxin B1 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects*; D004952:Esters / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects*
chemical_list: C570215:8,9-dihydroxy-8,9-dihydro-aflatoxin B1; D004952:Esters; D009153:Mutagens; D004247:DNA; C427203:calf thymus DNA; D016604:Aflatoxin B1