@article{2f1ecb5499b74865914a2546c8f7a50a,
title = "Spin state control of the hepatic cytochrome P450 redox potential",
abstract = "We have measured the oxidation-reduction potential of isolated and partially purified cytochrome P450 from uninduced rat liver, both in the presence and absence of Type I substrates. Native P450 is found to have a potential of -300 mV with respect to the standard hydrogen electrode, while the addition of benzphetamine or hexabarbital increases the redox potential to -237 mV and -225 mV respectively. Quantitation of the thermally induced S = 1 2 to S = 5 2 spin transition of the ferric heme iron for this P450 preparation both substrate free as well as with bound benzphetamine and hexabarbital indicate an increase in the high spin (S = 5 2) fraction on the binding of Type I substrates. The relevant oxidation-reduction equilibria of the heme chromaphore are presented in terms of a thermodynamic model for the control of the observed cytochrome P450 redox potential through this modulation of the spin configuration of the five d-electrons of the ferric heme iron induced by the binding of Type I substrates.",
author = "Sligar, {S. G.} and Cinti, {D. L.} and Gibson, {G. G.} and Schenkman, {J. B.}",
note = "Funding Information: The substrate induced change in redox potential of bacterial cytochrome P450 is clearly reflected primarily in a modulation of the forward rate constant for electron transfer into the hemoprotein (40,41). It is thus suggested from the present studies that the binding of Type I substrates to hepatic cytochrome P450 could increase the rate of electron flow from NADPH-reductase to P450 by modulating the spin state equilibrium of the electron accepting cytochrome. As this redox transfer process is rate limiting for some substrates in hepatocyte metabolism, the heme iron spin equilibrium could be of prime importance in the regulation of monoxygenase activity. Investigations are currently in progress in our laboratories to determine the method of control of electron flow in oxidative disposition in hepatocytes. Acknowledgements We would like to gratefully acknowledge open collaborative arrangements with Drs. Gunsalus, Douzou, Debey, and Ruckpaul, the expert technical assistance of MS Lydia Polomski, and the editorial help of MS B. Hutchinson which have greatly benefited this work. Supported in part by grants from the National Institutes of Health ~~24876 (SGS), GM26114 (JBS), and GM26530 (JBS,DLC). REFERENCES {"}Molecular Mechanisms of Oxygen Activation{"} Press, New York. Gunsalus, I., Pederson, T., and Sligar, S. (1977) Ann.Rev.Biochem. 44, 377. Omura, T., Sato, R., Cooper, D., Rosenthal, I. and Estabrook, R. (1965) Fed. Proc. Amer. Sot. Exp. Biol. &, 1181. 4. Ullrich, V. (ed.)(1977) llMicrosomes and Drug Oxidations{"} Yasuicochi, Y. and Masters B. S. (1976) J. Biol. Chem. Iyanagi, T., Makino, N., &d Mason H. (1974) Biochemistry Vermilion, J. and Coon, M. (1978) ;. Biol. Chem. 252, 2694. Sharrock, M., Munck, E., DeBrunner, P., Marshall, V., Lipscomb, M., and Gunsalus, I. (1973) Biochemistry I& 258. Champion, P., Lipscomb, J., Munck, E., DeBrunner, (1975) Biochemistry 16, 4151. 10. Gunsalus, I. C., Wagner, G. and Sligar, S. (1978) in {"}Metal Ions in Biological Systems{"} (H. Siegel, ed.) Marcel Dekker, New York. 11. Peterson, J. and Griffin, B. W. (1973) Drug Metabolism and Disposition 12. Peterson, J. A. (1971) Arch. Biochem. Biophys. 144, 678. 13. Lang, R., Hui Bon Hoa, G., Debey, P., and Gunsalus, I. C. (1977) Eur. J. Biochem. 77, 479. 14. Lang, R., Bonfils, C., and Debey, P. (1977) Eur. J. Biochem. 79, 623. 15. Lang, R., Hui Bon Hoa, G., Debey, P., and Gunsalus, I. C. (1979) Eur. J. Biochem. 94, 491.",
year = "1979",
month = oct,
day = "12",
doi = "10.1016/0006-291X(79)91916-8",
language = "English (US)",
volume = "90",
pages = "925--932",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Elsevier B.V.",
number = "3",
}