Inter-individual differences in the metabolism of environmental toxicants: cytochrome P 450 1A2 as a prototype
Identifieur interne : 003660 ( Main/Exploration ); précédent : 003659; suivant : 003661Inter-individual differences in the metabolism of environmental toxicants: cytochrome P 450 1A2 as a prototype
Auteurs : F. Peter Guengerich [États-Unis] ; Asit Parikh [États-Unis] ; Robert J. Turesky [Suisse] ; P. David Josephy [Canada]Source :
- Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis [ 0027-5107 ] ; 1999.
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.
Url:
DOI: 10.1016/S1383-5742(99)00039-3
Affiliations:
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Peter Guengerich</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Medical Research Building I, 23rd Avenue South at Pierce, Nashville, TN 37232-0146</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Parikh, Asit" sort="Parikh, Asit" uniqKey="Parikh A" first="Asit" last="Parikh">Asit Parikh</name><affiliation wicri:level="2"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Medical Research Building I, 23rd Avenue South at Pierce, Nashville, TN 37232-0146</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Turesky, Robert J" sort="Turesky, Robert J" uniqKey="Turesky R" first="Robert J." last="Turesky">Robert J. 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David Josephy</name><affiliation wicri:level="1"><country>Canada</country><wicri:regionArea>Guelph-Waterloo Centre for Graduate Work in Chemistry, Department of Chemistry and Biochemistry, University of Guelph, Guelph, Ontario</wicri:regionArea><wicri:noRegion>Ontario</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis</title><title level="j" type="abbrev">MUT</title><idno type="ISSN">0027-5107</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="1999">1999</date><biblScope unit="volume">428</biblScope><biblScope unit="issue">1–2</biblScope><biblScope unit="page" from="115">115</biblScope><biblScope unit="page" to="124">124</biblScope></imprint><idno type="ISSN">0027-5107</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0027-5107</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><affiliations><list><country><li>Canada</li><li>Suisse</li><li>États-Unis</li></country><region><li>Canton de Vaud</li><li>Tennessee</li></region><settlement><li>Lausanne</li></settlement></list><tree><country name="États-Unis"><region name="Tennessee"><name sortKey="Guengerich, F Peter" sort="Guengerich, F Peter" uniqKey="Guengerich F" first="F. Peter" last="Guengerich">F. 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