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Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants.

Publication ,  Journal Article
Han, J-F; He, X-Y; Herrington, JS; White, LA; Zhang, J-F; Hong, J-Y
Published in: Drug metabolism and disposition: the biological fate of chemicals
April 2008

Human cytochrome P450 1B1 (CYP1B1) plays a critical role in the metabolic activation of a variety of procarcinogens, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The existence of human CYP1B1 missense genetic variants has been demonstrated, but their activities in metabolizing PhIP are unknown. In this study, we expressed 15 naturally occurring CYP1B1 variants (with either single or multiple amino acid substitutions) and determined their activity changes in metabolizing PhIP to its two major metabolites, 2-hydroxyamino-PhIP and 4'-hydroxy-PhIP. Although the PhIP-metabolizing activities of four variants (Ala(119)Ser, Pro(379)Leu, Ala(443)Gly, Arg(48)Gly/Leu(432)Val) were comparable with that of the expressed wild-type CYP1B1, five variants (Trp(57)Cys, Gly(61)Glu, Arg(48)Gly/Ala(119)Ser, Arg(48)Gly/Ala(119)Ser/Leu(432)Val, Arg(48)Gly/Ala(119)Ser/Leu(432)Val/Ala(443)Gly) exhibited more than 2-fold decrease in activity and a reduction in the catalytic efficiency (V(max)/K(m)) for both N- and 4-hydroxylation of PhIP. Six variants (Gly(365)Trp, Glu(387)Lys, Arg(390)His, Pro(437)Leu, Asn(453)Ser, Arg(469)Trp) showed little activity in PhIP metabolism, but the molecular mechanisms involved are apparently different. The microsomal CYP1B1 protein level was significantly decreased for the Trp(365), Lys(387), and His(390) variants and was not detectable for the Ser(453) variant. In contrast, there was no difference between the Trp(469) variant and the wild-type in the microsomal CYP1B1 protein level and P450 content but the Trp(469) variant totally lost its metabolic activity toward PhIP. The Leu(437) variant also had a substantial amount of CYP1B1 protein in the microsomes, but there was a lack of detectable P450 peak and activity. Our results should be useful in selecting appropriate CYP1B1 variants as cancer susceptibility biomarkers for human population studies related to PhIP exposure.

Duke Scholars

Published In

Drug metabolism and disposition: the biological fate of chemicals

DOI

EISSN

1521-009X

ISSN

0090-9556

Publication Date

April 2008

Volume

36

Issue

4

Start / End Page

745 / 752

Related Subject Headings

  • Species Specificity
  • Rats
  • Pharmacology & Pharmacy
  • Microsomes
  • Metabolic Networks and Pathways
  • Insecta
  • Imidazoles
  • Humans
  • Genetic Variation
  • Cytochrome P-450 Enzyme System
 

Citation

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Han, J.-F., He, X.-Y., Herrington, J. S., White, L. A., Zhang, J.-F., & Hong, J.-Y. (2008). Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 36(4), 745–752. https://doi.org/10.1124/dmd.107.016824
Han, Jing-Fen, Xiao-Yang He, Jason S. Herrington, Lori A. White, Jun-Feng Zhang, and Jun-Yan Hong. “Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants.Drug Metabolism and Disposition: The Biological Fate of Chemicals 36, no. 4 (April 2008): 745–52. https://doi.org/10.1124/dmd.107.016824.
Han J-F, He X-Y, Herrington JS, White LA, Zhang J-F, Hong J-Y. Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants. Drug metabolism and disposition: the biological fate of chemicals. 2008 Apr;36(4):745–52.
Han, Jing-Fen, et al. “Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants.Drug Metabolism and Disposition: The Biological Fate of Chemicals, vol. 36, no. 4, Apr. 2008, pp. 745–52. Epmc, doi:10.1124/dmd.107.016824.
Han J-F, He X-Y, Herrington JS, White LA, Zhang J-F, Hong J-Y. Metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) by human CYP1B1 genetic variants. Drug metabolism and disposition: the biological fate of chemicals. 2008 Apr;36(4):745–752.

Published In

Drug metabolism and disposition: the biological fate of chemicals

DOI

EISSN

1521-009X

ISSN

0090-9556

Publication Date

April 2008

Volume

36

Issue

4

Start / End Page

745 / 752

Related Subject Headings

  • Species Specificity
  • Rats
  • Pharmacology & Pharmacy
  • Microsomes
  • Metabolic Networks and Pathways
  • Insecta
  • Imidazoles
  • Humans
  • Genetic Variation
  • Cytochrome P-450 Enzyme System