Inter-individual differences in the metabolism of environmental toxicants: Cytochrome P450 1A2 as a prototype

F. Peter Guengerich, Asit Parikh, Robert J. Turesky, P. David Josephy

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Abstract

Cytochrome P450 (P450) 1A2 provides an interesting paradigm for inter-individual differences in the metabolism of pro-carcinogens. The enzyme is known to vary 40-fold among individuals and may contribute to cancers caused by heterocyclic amines and other chemicals. Rat and human P450 1A2 are known to be 75% identical and were compared for several catalytic activities. The human enzyme was an order of magnitude more efficient in the N-hydroxylation of two heterocyclic amines. Further, the levels of P450 1A2 expressed in human livers show a 40-fold variation, with some as high as 0.25 nmol P450 1A2 per milligram microsomal protein. Some human liver samples are more active (than those isolated from polychlorinated biphenyl-treated rats) in the activation of heterocyclic amines. A bacterial genotoxicity assay has been developed in which human P450 1A2 and NADPH-P450 reductase are expressed within Escherichia coli and bacterial mutants can be assayed using reversion to lac prototrophy. A random mutagenesis strategy for human P450 1A2 has been developed and used to examine the changes in catalytic activity seen with many single-amino acid substitutions. These results may be of relevance in consideration of genetic polymorphisms. Further, the findings pose a challenge to molecular epidemiology effort in that results with one substrate do not necessarily predict those for others. Some dinitropyrenes are P450 1A2 substrates but others are not. 6-Nitrochrysene can be activated by human P450 1A2 but the (mono) nitropyrenes examined were not; these were oxidized by P450 3A4 instead. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume428
Issue number1-2
DOIs
StatePublished - Jul 16 1999

Bibliographical note

Funding Information:
This research has been supported in part by USPHS grants R35 CA44353, P30 ES00267 (F.P.G.), and T32 GM07347 (A.P., F.P.G.) and a grant from NSERC Canada (P.D.J.). We express our appreciation to Dr. T. Shimada, who has been involved in many aspects of our ongoing efforts with heterocyclic amines, and Dr. F.F. Kadlubar, who has been involved in many of these activities with P450 1A2. Thanks are also extended to Prof. W. Au for his invitation.

Keywords

  • Cytochrome P450, 1A2
  • Cytochrome P450, human
  • Dinitropyrene
  • Escherichia coli, expression of proteins in
  • Genetoxicity assay
  • Heterocyclic amine
  • Mutagenesis, random

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