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Regioselectivity preference of testosterone hydroxylation by cytochrome P450 3A4

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Abstract

Theoretical studies are presented into the experimentally observed regioselectivity difference of testosterone hydroxylation by cytochrome P450 3A4 at the 1β, 2β, 6β, and 15β positions. Such regioselectivity is investigated by density functional theory calculations on a model system. The barrier heights of hydrogen abstraction, which are corrected by zero-point vibrational energies, are computed to be about 10.1, 13.6, 14.4, and 16.2 kcal/mol for the 6β-, 2β-, 15β-, and 1β-positions, respectively. The calculated barriers suggest the regioselectivity preference of 6β ≫ 2β > 15β > 1β, which is in good agreement with experimental findings.

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Acknowledgments

This research is supported by the Research Corporation. We thank the National Cancer Institute-Frederick Advanced Biomedical Computing Center for providing CPU time and access to the Gaussian03 program. We thank Dr. Hoyt Meyer for critically reading the manuscript.

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  1. Jeffery Kim

    Present address: Rush University Medical College, Chicago, IL, 60612, USA

Authors and Affiliations

  1. Chemistry Department, University of Colorado Denver, PO Box 173364, Denver, CO, 80217, USA

    Yan Zhang, Phani Morisetti, Jeffery Kim, Lynelle Smith & Hai Lin

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  1. Yan Zhang
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Correspondence to Hai Lin.

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Zhang, Y., Morisetti, P., Kim, J. et al. Regioselectivity preference of testosterone hydroxylation by cytochrome P450 3A4. Theor Chem Account 121, 313–319 (2008). https://doi.org/10.1007/s00214-008-0480-1

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