Differential metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in mice humanized for CYP1A1 and CYP1A2.

The procarcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine formed during the cooking of foods. Metabolism of PhIP by CYP1A2 differs substantially between humans and rodents, with more N2-hydroxylation (activation) and less 4'-hydroxylation (detoxication) in humans. Therefore, the human response to PhIP and other heterocyclic amine exposure may not be accurately reflected in the laboratory rodent. By generating mouse models expressing the human genes, species differences in heterocyclic 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-null background (hCYP1A2). Expression of human CYP1A2 protein was detected in the liver and also 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 human CYP1A1 and CYP1A2 protein in the liver. Differences in the metabolism of the heterocyclic amine PhIP were observed between wild-type and hCYP1A2 mice. PhIP was preferentially metabolized by N2-hydroxylation in hCYP1A2 mice, whereas in wild-type mice, 4'-hydroxylation was the predominant pathway. Since the N2-hydroxylation pathway for PhIP metabolism has been reported to be predominant in humans, these results illustrate the potential effectiveness of using these transgenic, humanized mice as models for determining human health risks to PhIP and other heterocyclic amines instead of wild-type mice.