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Related Experiment Videos

Molecular basis for a functionally unique cytochrome P450IIB1 variant.

K M Kedzie1, C A Balfour, G Y Escobar

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson 85721.

The Journal of Biological Chemistry
|November 25, 1991
PubMed
Summary

Cytochrome P450IIB1 variants in Wistar Munich rats show altered androstenedione metabolism due to a Gly-478 to Ala substitution. This single amino acid change significantly impacts enzyme activity and substrate specificity, influencing drug metabolism pathways.

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Area of Science:

  • Biochemistry
  • Pharmacology
  • Genetics

Background:

  • Phenobarbital induces cytochrome P450IIB1 in rat liver microsomes.
  • Inbred rat strains exhibit allelic variants of cytochrome P450IIB1.
  • Cytochrome P450IIB1 plays a crucial role in xenobiotic and endogenous compound metabolism.

Purpose of the Study:

  • To characterize the functional differences of cytochrome P450IIB1 allelic variants.
  • To investigate the catalytic properties of P450IIB1 from Wistar Munich rats.
  • To identify the molecular basis for altered P450IIB1 activity.

Main Methods:

  • Analysis of liver microsomes from phenobarbital-treated rats of four inbred strains.
  • Enzyme activity assays, including androstenedione 16 beta-hydroxylase and 7-ethoxycoumarin deethylase.

Related Experiment Videos

  • Purification and characterization of P450IIB1 variants.
  • Cloning, sequencing, and heterologous expression of P450IIB1 cDNA.

    • Main Results:

    • Wistar Munich (WM) strain showed 5- to 10-fold lower androstenedione 16 beta-hydroxylase activity.
    • WM P450IIB1 was refractory to inactivation by a selective P450IIB1 inactivator.
    • Purified P450IIB1-WM exhibited altered substrate specificity and stereoselectivity in hydroxylation.
    • A single amino acid substitution (Gly-478 to Ala) was identified in P450IIB1-WM.
    • Heterologous expression confirmed distinct metabolite profiles for P450IIB1 and P450IIB1-WM.

    Conclusions:

    • The Gly-478 to Ala substitution in P450IIB1-WM is responsible for its distinct catalytic properties.
    • This allelic variant exhibits significantly altered substrate metabolism compared to other P450IIB1 forms.
    • The findings highlight the impact of single amino acid changes on cytochrome P450 enzyme function and substrate selectivity.