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Effect of Human Cytochrome P450 2D6 Polymorphism on Progesterone Hydroxylation

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Abstract

Background and Objectives

Herein, hydroxylation activities at the 6β-position and 21-position of progesterone mediated by human cytochrome P450 (CYP) 2D6 and its variants and the effects of psychotropic drugs on these hydroxylation activities were compared to clarify whether CYP2D6 polymorphisms and psychotropic drugs impact neurosteroid levels in the brain.

Methods

Progesterone was incubated with CYP2D6.1, CYP2D6.2 (Arg296Cys, Ser486Thr), CYP2D6.10 (Pro34Ser, Ser486Thr), and CYP2D6.39 (Ser486Thr) in the absence or presence of typical psychotropic drugs (fluvoxamine, fluoxetine, paroxetine, fluphenazine, and milnacipran) and endogenous steroids (testosterone and cortisol). Then, 6β- and 21-hydroxyprogesterone levels were determined by high-performance liquid chromatography.

Results

Although the Michaelis-Menten constants (Km) for progesterone 6β- and 21-hydroxylation reactions mediated by the different CYP2D6 variants were similar, the maximal velocity (Vmax) values of the reactions mediated by CYP2D6.1 and CYP2D6.2 were the highest, followed by those mediated by CYP2D6.39 and CYP2D6.10. Thus, the of progesterone 6β- and/or 21-hydroxylation reactions mediated by CYP2D6.1 and CYP2D6.2 showed the highest Vmax/Km values, followed by the reactions mediated by CYP2D6.39. All investigated compounds inhibited progesterone 21-hydroxylation mediated by CYP2D6 variants at high concentrations. Interestingly, at low concentrations, fluoxetine increased progesterone 21-hydroxylation mediated by CYP2D6.1, but not that mediated by CYP2D6.2 or CYP2D6.10. In addition, the Km value for CYP2D6.2 was elevated in the presence of fluoxetine, whereas the value for CYP2D6.1 was unaltered; however, Vmax values of both CYP2D6.1 and CYP2D6.2 were increased. Paroxetine competitively inhibited CYP2D6.1- and CYP2D6.2-mediated progesterone 21-hydroxylation.

Conclusions

These results suggest that CYP2D6 polymorphism can affect the stimulation/inhibition of progesterone 21-hydroxylation.

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We would like to thank Editage (www.editage.com) for English language editing.

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Authors and Affiliations

  1. School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan

    Toshiro Niwa, Shoko Sasaki, Yuka Yamamoto & Mayu Tanaka

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  1. Toshiro Niwa
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Correspondence to Toshiro Niwa.

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Author Contributions

Participated in research design: TN and SS. Conducted experiments: TN, SS, YY, and MT. Performed data analysis: TN, SS, YY, and MT. Wrote or contributed to the writing of the manuscript: TN.

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Niwa, T., Sasaki, S., Yamamoto, Y. et al. Effect of Human Cytochrome P450 2D6 Polymorphism on Progesterone Hydroxylation. Eur J Drug Metab Pharmacokinet 47, 741–747 (2022). https://doi.org/10.1007/s13318-022-00784-7

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