Kunihiko F. Miura

Cytogenetic effects of a food mutagen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and its metabolite, 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), on human and Chinese hamster cells in vitro

2-Amino-1-methyl-6-phenylimidazo[4,5-beta]pyridine (PhIP) induced structural chromosomal aberrations (CAs) and sister-chromatid exchanges (SCEs) in human lymphocytes and human diploid fibroblasts (TIG-7) at concentrations above 12.5 microgram /ml in the presence of rat S9 mix. PhIP also elevated the frequencies of SCEs in human lymphocytes in the presence of rat S9 at concentrations above 2.0 microgram/ml with dose-dependency. A proximate form of metabolites of PhIP, 2-hydroxy-amino-1-methyl-6-phenylimidazo[4,5-beta]pyridine (N-OH-PhIP), caused CAs in human and Chinese hamster fibroblast cells in the absence of S9 mix at concentrations above 0.75 microgram/ml and 1.25 microgram/ml, respectively, which were 10 times lower than the effective concentration of PhIP. No marked differences were observed in the cytogenetic sensitivity to N-OH-PhIP between human and Chinese hamster cells, except between lymphocytes obtained from different donors.

The possible role of acetyltransferase in the induction of cytogenetic effects by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in cultured Chinese hamster cells

When metabolically activated, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine isolated from cooked food, is clastogenic in cultured Chinese hamster and human cells. Secondary metabolites of PhIP are formed via acetyltransferase (AT) and sulfotransferase (ST) activity; however, which is responsible for its clastogenic effect is unknown. We addressed this question. We used a parental Chinese hamster lung cell line and three sublines transfected with different AT genes to test the clastogenic (i.e., micronucleus-inducing) effects of metabolically activated PhIP and 7,12-dimethylbenz[a]anthracene (DMBA) in the presence and absence of pentachlorophenol (PCP), a ST inhibitor. PhIP was significantly more clastogenic in the three AT-enriched sublines than in the parental line (p < 0.001). DMBA (a ST-activated mutagen), on the other hand, equally induced MNs in all the cell lines. When PCP was added to the test system, the MN-induction ability of DMBA, but not of PhIP, decreased significantly (p < 0.001). These findings strongly suggest that PhIP clastogenicity is due to AT activity and not to ST activity.