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

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