Differential Metabolism of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in Mice Humanized for CYP1A1 and CYP1A2

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• 作者：Connie Cheung ; Xiaochao Ma ; Kristopher W. Krausz ; Shioko Kimura ; Lionel Feigenbaum ; Timothy P. Dalton ; Daniel W. Nebert ; Jeffrey R. Idle ; and Frank J. Gonzalez
• 刊名：Chemical Research in Toxicology
• 出版年：2005
• 出版时间：September 2005
• 年：2005
• 卷：18
• 期：9
• 页码：1471 - 1478
• 全文大小：424K
• 年卷期：v.18,no.9(September 2005)
• ISSN：1520-5010

文摘

The procarcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the mostabundant heterocyclic amine formed during the cooking of foods. Metabolism of PhIP byCYP1A2 differs substantially between humans and rodents, with more N²-hydroxylation(activation) and less 4'-hydroxylation (detoxication) in humans. Therefore, the human responseto PhIP and other heterocyclic amine exposure may not be accurately reflected in the laboratoryrodent. By generating mouse models expressing the human genes, species differences inheterocyclic amine metabolism can be addressed. Two transgenic mouse lines were developed,one expressing the human CYP1A1 CYP1A2 transgene in a mouse Cyp1a1-null background(hCYP1A1) and another expressing human CYP1A1 CYP1A2 in a mouse Cyp1a2-nullbackground (hCYP1A2). Expression of human CYP1A2 protein was detected in the liver andalso at considerably lower levels in extrahepatic tissues such as lung, kidney, colon, and heart.In the hCYP1A1 and hCYP1A2 mice, 3-methylcholanthrene (3-MC) induced both humanCYP1A1 and CYP1A2 protein in the liver. Differences in the metabolism of the heterocyclicamine PhIP were observed between wild-type and hCYP1A2 mice. PhIP was preferentiallymetabolized by N ²-hydroxylation in hCYP1A2 mice, whereas in wild-type mice, 4'-hydroxylationwas the predominant pathway. Since the N²-hydroxylation pathway for PhIP metabolism hasbeen reported to be predominant in humans, these results illustrate the potential effectivenessof using these transgenic, humanized mice as models for determining human health risks toPhIP and other heterocyclic amines instead of wild-type mice.