PubMed:17295238 JSONTXT

{"project":"bionlp-st-epi-2011-training","denotations":[{"id":"T1","span":{"begin":141,"end":147},"obj":"Protein"},{"id":"T2","span":{"begin":177,"end":198},"obj":"Protein"},{"id":"T3","span":{"begin":399,"end":417},"obj":"Protein"},{"id":"T4","span":{"begin":466,"end":487},"obj":"Protein"},{"id":"T5","span":{"begin":489,"end":493},"obj":"Protein"},{"id":"T6","span":{"begin":602,"end":608},"obj":"Protein"},{"id":"T7","span":{"begin":620,"end":624},"obj":"Protein"},{"id":"T8","span":{"begin":649,"end":653},"obj":"Protein"},{"id":"T9","span":{"begin":684,"end":690},"obj":"Protein"},{"id":"T10","span":{"begin":695,"end":699},"obj":"Protein"},{"id":"T11","span":{"begin":772,"end":778},"obj":"Protein"},{"id":"T12","span":{"begin":855,"end":861},"obj":"Protein"},{"id":"T13","span":{"begin":909,"end":913},"obj":"Protein"},{"id":"T14","span":{"begin":1083,"end":1087},"obj":"Protein"},{"id":"T15","span":{"begin":1215,"end":1254},"obj":"Protein"},{"id":"T16","span":{"begin":1256,"end":1260},"obj":"Protein"},{"id":"T17","span":{"begin":1279,"end":1285},"obj":"Protein"},{"id":"T18","span":{"begin":1328,"end":1332},"obj":"Protein"},{"id":"T19","span":{"begin":1338,"end":1342},"obj":"Protein"},{"id":"T20","span":{"begin":1607,"end":1613},"obj":"Protein"},{"id":"T21","span":{"begin":1633,"end":1639},"obj":"Protein"},{"id":"T22","span":{"begin":1644,"end":1648},"obj":"Protein"},{"id":"T23","span":{"begin":1671,"end":1677},"obj":"Protein"},{"id":"T24","span":{"begin":1682,"end":1686},"obj":"Protein"},{"id":"T25","span":{"begin":1818,"end":1824},"obj":"Protein"},{"id":"T26","span":{"begin":1825,"end":1829},"obj":"Protein"},{"id":"T27","span":{"begin":1839,"end":1845},"obj":"Protein"},{"id":"T28","span":{"begin":1846,"end":1850},"obj":"Protein"},{"id":"T29","span":{"begin":1909,"end":1915},"obj":"Protein"},{"id":"T30","span":{"begin":1996,"end":2000},"obj":"Protein"}],"text":"2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine-induced DNA adducts and genotoxicity in chinese hamster ovary (CHO) cells expressing human CYP1A2 and rapid or slow acetylator N-acetyltransferase 2.\nHeterocyclic amine carcinogens such as 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) are present in diet and cigarette smoke. Bioactivation in humans includes N-hydroxylation catalyzed by cytochrome P4501A2 possibly followed by O-acetylation catalyzed by N-acetyltransferase 2 (NAT2). Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. CYP1A2 and NAT2 catalytic activities were undetectable in untransfected CHO cell lines. CYP1A2 catalytic activity levels did not differ significantly (P \u003e 0.05) among the CYP1A2-transfected cell lines. Cells transfected with NAT2*4 had significantly higher levels of N-acetyltransferase (P = 0.0001) and N-hydroxy-PhIP O-acetyltransferase (P = 0.0170) catalytic activity than cells transfected with NAT2*5B. PhIP caused dose-dependent decreases in cell survival and significant (P \u003c 0.001) increases in mutagenesis measured at the hypoxanthine phosphoribosyl transferase (hprt) locus in all the CYP1A2-transfected cell lines. Transfection with NAT2*4 or NAT2*5B did not further increase hprt mutagenesis. PhIP-induced hprt mutant cDNAs were sequenced, and 80% of the mutations were single base substitutions at G:C base pairs. dG-C8-PhIP DNA adduct levels were dose-dependent in the order: untransfected \u003c transfected with CYP1A2 \u003c transfected with CYP1A2 and NAT2*5B \u003c transfected with CYP1A2 and NAT2*4. Following incubation with 1.2 microM PhIP, DNA adduct levels were significantly (P \u003c 0.05) higher in CHO cells transfected with CYP1A2/NAT2*4 versus CYP1A2/NAT2*5B. These results strongly support an activation role for CYP1A2 in PhIP-induced mutagenesis and DNA damage and suggest a modest effect of human NAT2 and its genetic polymorphism on PhIP DNA adduct levels."}