ORGAN DISTINCTIVE MUTAGENICITY IN MUTA(TM)MOUSE AFTER SHORT-TERM EXPOSURE TO PHIP

We have investigated PhIP-induced mutagenicity in various tissues (kid ney, liver, large and small intestine) using a transgenic mouse model (Muta(TM)Mouse), In addition to tissue specific mutagenesis, we measur ed the binding of [C-14]PhIP to Muta(TM)Mouse mice blood proteins (hae moglobin and albumin), to obtain a quantitative estimate of carcinogen exposure and activation and their relationship to mutagenesis, Short- term (4 days) treatment of Muta(TM)Mouse mice with [C-14]PhIP by oral gavage resulted in the dose-dependent accumulation of radiolabelled ma terial bound to haemoglobin and serum albumin, PhIP, at the highest do se (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 live r, However, there was no significant increase in mutations in the kidn ey at this dose. In contrast, there were no significant differences in any of these tissues between the vehicle control and the two lower do ses (2.0 and 0.2 mg/kg respectively), These results are discussed in r elationship to those previously reported for PhIP at the Dlb-1 locus.