Organ distinctive mutagenicity in MutaMouse after short-term exposure to PhIP.
We have investigated PhIP-induced mutagenicity in various tissues (kidney, liver, large and small intestine) using a transgenic mouse model (MutaMouse). In addition to tissue specific mutagenesis, we measured the binding of [14C]PhIP to MutaMouse mice blood proteins (haemoglobin and albumin), to obtain a quantitative estimate of carcinogen exposure and activation and their relationship to mutagenesis. Short-term (4 days) treatment of MutaMouse mice with [14C]PhIP by oral gavage resulted in the dose-dependent accumulation of radiolabelled material bound to haemoglobin and serum albumin. PhIP, at the highest dose (20 mg/kg), caused a 5.9-fold increase in the mutation frequency in the large intestine, a 4.2-fold increase in the mutation frequency in the small intestine but only a marginal 1.6-fold increase in the liver. However, there was no significant increase in mutations in the kidney at this dose. In contrast, there were no significant differences in any of these tissues between the vehicle control and the two lower doses (2.0 and 0.2 mg/kg respectively). These results are discussed in relationship to those previously reported for PhIP at the Dlb-1 locus.
Lynch
A M
AM
Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, UK.
Gooderham
N J
NJ
Boobis
A R
AR
D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000378:metabolism; D007093:Imidazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D008957:Models, Genetic; D016296:Mutagenesis; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000493:pharmacokinetics / Q000633:toxicity*; D009154:Mutation; D012709:Serum Albumin / Q000378:metabolism; D013057:Spectrum Analysis / Q000379:methods; D014018:Tissue Distribution; D019076:Transgenes; D001616:beta-Galactosidase / Q000187:drug effects / Q000235:genetics
D002250:Carbon Radioisotopes; D002273:Carcinogens; D006454:Hemoglobins; D007093:Imidazoles; D009153:Mutagens; D012709:Serum Albumin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; D001616:beta-Galactosidase