title: Developmental changes in hepatic activation of dietary mutagens by mice.
abstract: Metabolic activation of the food mutagens 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) and aflatoxin B1 by female BALB/c mice of different ages (2-24 weeks) was investigated in vivo and in vitro using Salmonella typhimurium TA98 as the indicator organism. The in vivo activation of the three mutagens was investigated in 4- and 24-week-old mice using an intrasanguineous host-mediated assay. All three compounds showed reduced levels of activation with the older hosts. Hepatic S9 fractions from female mice of varying ages between 2 and 24 weeks were used in the in vitro mutagenicity assay. To achieve optimal activation to bacterial mutagens, 5% S9 was required for aflatoxin B1 and Trp-P-2 and 10% S9 for MeIQ; age of donor generally had little effect on the profile of these protein activation curves. Under these optimal conditions MeIQ and Trp-P-2 both exhibited, as before, age-dependent decreases in activation over a wide range of mutagen concentrations, however the in vitro activation of aflatoxin showed no consistent change with age. Spectrophotometric measurements of S9 cytochrome P-450 content showed a decrease in concentration with increasing age, but this was not sufficient to account for changes observed in hepatic mutagen activation. However, changes in the activities of certain cytochrome P-450 isoenzymes and cytosolic GSH-transferases, which in turn result in changes in the activation and detoxification capacity of the liver, would appear to explain age-dependent changes in the activity of mutagens in vivo.
authors.affiliation: Department of Biochemistry, University College, London, U.K.
authors.forename: W E
authors.initials: WE
authors.lastname: Brennan-Craddock
authors.forename: S
authors.initials: S
authors.lastname: Neale
authors.forename: A K
authors.initials: AK
authors.lastname: Mallett
authors.forename: I R
authors.initials: IR
authors.lastname: Rowland
mesh_terms: D016604:Aflatoxin B1; D000348:Aflatoxins / Q000493:pharmacokinetics*; D000375:Aging / Q000378:metabolism; D000818:Animals; D001711:Biotransformation; D002243:Carbolines / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005506:Food Contamination; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009152:Mutagenicity Tests; D009153:Mutagens; D011804:Quinolines / Q000493:pharmacokinetics*
chemical_list: D000348:Aflatoxins; D002243:Carbolines; D009153:Mutagens; D011804:Quinolines; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole; D003577:Cytochrome P-450 Enzyme System; D016604:Aflatoxin B1; D005982:Glutathione Transferase; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline