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Genotoxicity of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): formation of 2-hydroxamino-PhIP, a directly acting genotixic metabolite
Department of Toxicology, National Institute of Public Health Geitmyrsveien 75, N-0462 Oslo 4, Norvay
Hepatocytes isdated from Aroclor 1254 (PCB) pretreated rats metabolized 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP) to a reactive metabolite that induced DNA damage measured by alkaline elution or as increased unscheduled DNA synthesis. PhIP induced mutations in Salmonella typhimuniun TA98 and DNA strand breaks and sister chromatid exchange(s) in Chinese hamster V79 cells co-incubated with PCR-hepatocytes. No, or only minor genotoxic, effects were observed when hepatocytes from non-induced rats were used. The bacterial mutagenicity could be inhibited by 
-naphthoflavone, indicating a role of P-450 in the activation of PhIP. At least eight different metabolites could be separated on HPLC after PhIP had been incubated with PCB-hepatocytes. All of the directly acting mutagenicity towards S.typhimurium TA98 co-eluted with one of the metabolites. The identity of this metabolite was concluded to be 2-hydroamino-PhIP based on the following evidence: (i) it reduced ferric ion to ferrous ion as hydroxylamines do, (ii) it had an identical UV spectrum and chromatographic properties as a species formed upon redudion of 2-nitro-PhIP by NADPH P-450 reductase. This product displayed a major peak at m/z 241 during thermospray mass spectrometry in the positive-ion mode as would be expected from 2-hydroxamino-PhIP. 2-Hydroxamino-PhIP was directly genotoxic both to TA98 and V79 cells. The genotoxic activity of the medium after removing the hepatocytes remained stable for several hours. Compared to 2-amino-3,4-dimethylimidazo-[4,5-f]quinoline (MeIQ), PhIP caused a much larger increase in DNA damage in V79 cells (with hepatocyte activation), whereas MeIQ was more potent with respect to DNA damage induced in hepatocytes and bacteria.
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