ANALYSIS OF MUTATIONS INDUCED BY 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE (PHIP) IN HUMAN LYMPHOBLASTOID-CELLS

被引:53
|
作者
MORGENTHALER, PML
HOLZHAUSER, D
机构
[1] Nestec Ltd., Research Centre, Quality and Safety Assurance Department, 1000 Lausanne 26, PO Box 44, Vers-Chez-les-Blanc
关键词
D O I
10.1093/carcin/16.4.713
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), a heterocyclic aromatic amine that is formed in abundance in cooked meats, has been found to be mutagenic in human lymphoblastoid TK6 cells at the thymidine kinase and hypoxanthine-guanine phosphoribosyl transferase (hgprt) loci, The mutations induced at the hgprt locus have been analysed, Of the mutations that have been identified, 60% were found in the coding sequence of the gene, Forty percent were in the introns which resulted in aberrant splicing and consequently, leading to exon losses in the mature hprt mRNA. Mutations resulting in a loss of exonIII appeared most frequently followed by losses of exonVI, exonVIII and partial loss of exonIX. All identified mutations occurred at GC base pairs, consistent with the adducts of PhIP that have been found previously and suggesting that the N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, (dG-C8-PhIP) adduct may be the premutagenic lesion, Most of the mutations are GC-->TA transversions except for a cluster of single base pair deletions in a run of guanines. There appears to be strand bias in the induction of mutations with 85% of the mutations on the non-transcribed strand, Although the number of mutations analysed is limited (54 mutants), there are several sites (positions 166 and 207 of the coding sequence, and the splice acceptor site of exonIII) which are overrepresented, There is a preference for a 5'purine but not a strong bias for 3'A as has been found for other mutagens that form a premutagenic lesion at G. Triplet analysis shows that the triplets, 5'GGA3' and 5'AGG3', where the middle base is mutated are preferred.
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页码:713 / 718
页数:6
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