TY - JOUR
T1 - Activation of heterocyclic aromatic amines by rat and human liver microsomes and by purified rat and human cytochrome P450 1A2
AU - Turesky, Robert J.
AU - Constable, Anne
AU - Richoz, Janique
AU - Varga, Nathalia
AU - Markovic, Jovanka
AU - Martin, Martha V.
AU - Guengerich, F. Peter
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1998
Y1 - 1998
N2 - The dietary mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are activated to genotoxins by rat and human liver cytochrome P450 (P450) 1A1- and 1A2-mediated N-oxidation. Immunoquantitation of 51 human liver samples revealed a wide range in P450 1A2 expression (10-250 pmol/mg of microsomal protein, median 71 pmol/mg), with 39% of the livers containing > 100 pmol/mg of protein. There was no evidence for expression of P450 1A1 (< 1 pmol/mg of protein). P450 1A2 levels were correlated to MeIQx and PhIP N-oxidation rates (r = 0.83, 0.73, respectively). In male Fischer-344 and Sprague-Dawley rats, hepatic P450 1A2 ranged from 5 to 35 pmol/mg of protein, while P450 1A1 was < 1 pmol/mg. Animal pretreatment with 3-methylcholanthrene, β-naphthoflavone, or polychlorinated biphenyls (PCB) resulted inasmuch as 340-fold and >1000- fold induction of P450 1A2 and 1A1, respectively, and a 220-fold increase in N-oxidation activity. Approximately 20% of the human samples were as active in N-oxidation and conversion of MeIQx to bacterial mutagens as microsomes of PCB-pretreated rats [3-4 nmol of NHOH-MeIQx formed min-1 (mg of protein)- 1]. In contrast, microsomes from PCB-treated rats displayed higher rates of PhIP N-oxidation and activation to mutagens than the most active human liver microsomes [8-24 vs 2-4 nmol of HNOH-PhIP formed min-1 (mg of protein)- 1]. Recombinant human P450 1A2 showed catalytic efficiencies of MeIQx and PhIP N-oxidation that were 10-19-fold higher than purified rat P450 1A2. Cytochrome P450 1A2 expression in rodent and human liver tissue varies greatly and there are considerable differences between the enzymes in the two species in the activation of some heterocyclic aromatic amines, which must be considered when assessing human health risk.
AB - The dietary mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are activated to genotoxins by rat and human liver cytochrome P450 (P450) 1A1- and 1A2-mediated N-oxidation. Immunoquantitation of 51 human liver samples revealed a wide range in P450 1A2 expression (10-250 pmol/mg of microsomal protein, median 71 pmol/mg), with 39% of the livers containing > 100 pmol/mg of protein. There was no evidence for expression of P450 1A1 (< 1 pmol/mg of protein). P450 1A2 levels were correlated to MeIQx and PhIP N-oxidation rates (r = 0.83, 0.73, respectively). In male Fischer-344 and Sprague-Dawley rats, hepatic P450 1A2 ranged from 5 to 35 pmol/mg of protein, while P450 1A1 was < 1 pmol/mg. Animal pretreatment with 3-methylcholanthrene, β-naphthoflavone, or polychlorinated biphenyls (PCB) resulted inasmuch as 340-fold and >1000- fold induction of P450 1A2 and 1A1, respectively, and a 220-fold increase in N-oxidation activity. Approximately 20% of the human samples were as active in N-oxidation and conversion of MeIQx to bacterial mutagens as microsomes of PCB-pretreated rats [3-4 nmol of NHOH-MeIQx formed min-1 (mg of protein)- 1]. In contrast, microsomes from PCB-treated rats displayed higher rates of PhIP N-oxidation and activation to mutagens than the most active human liver microsomes [8-24 vs 2-4 nmol of HNOH-PhIP formed min-1 (mg of protein)- 1]. Recombinant human P450 1A2 showed catalytic efficiencies of MeIQx and PhIP N-oxidation that were 10-19-fold higher than purified rat P450 1A2. Cytochrome P450 1A2 expression in rodent and human liver tissue varies greatly and there are considerable differences between the enzymes in the two species in the activation of some heterocyclic aromatic amines, which must be considered when assessing human health risk.
UR - http://www.scopus.com/inward/record.url?scp=0031815379&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031815379&partnerID=8YFLogxK
U2 - 10.1021/tx980022n
DO - 10.1021/tx980022n
M3 - Article
C2 - 9705755
AN - SCOPUS:0031815379
SN - 0893-228X
VL - 11
SP - 925
EP - 936
JO - Chemical research in toxicology
JF - Chemical research in toxicology
IS - 8
ER -