Mutant yields and mutational spectra of the heterocyclic amines MeIQ and PhIP at the S1 locus of human-hamster A(L) cells with activation by chick embryo liver (CELC) co-cultures

Cooking meat and fish at high temperature creates heterocyclic amines (HA) including 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Several HA are mutagens in th e Ames' S9/Salmonella assay. While PhIP is a substantial Ames' test mutagen , it is 1000-fold less active than the extraordinarily potent MeIQ. In cont rast, MeIQ is significantly less mutagenic than PhIP in several mammalian c ell assays, especially in repair-deficient Chinese hamster ovary (CHO) cell s. HA are suspect human carcinogens on the basis of (i) epidemiological evi dence, (ii) induction of tumors in rodents and monkeys, (iii) DNA adduct fo rmation and (iv) mutagenic capacity, In this study, MeIQ and PhIP were sign ificant mutagens at the S1 locus of co-cultivated human/hamster hybrid A(L) cells following metabolic activation by beta-napthoflavone (beta NF)-induc ed chick embryonic liver cultures (CELC). MeIQ was more mutagenic than PhIP in the CELC + A(L) cell assay. The mutant response curves increase with do se and then plateau (PhIP), or decrease (MeIQ). The inflections in these re sponse curves coincide with dose-dependent decreases in cytochrome CYP1A1 a ctivity. Molecular analysis of S1(-) mutants indicates that a substantial f raction, > 65%, of the mutations induced by PhIP are deletions of 4.2 to 13 3 (Mbp); half are larger than 21 Mbp. Mutations induced by MeIQ were smalle r, most (56%) being less than 5.7 Mop. When appropriate metabolic activatio n is combined with a target locus, which can detect both small and large ch romosomal mutations, both MeIQ and PhIP are significant mutagens and clasto gens in repair proficient mammalian cells. (C) 1999 Elsevier Science B.V. A ll rights reserved.