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Drug Metabolism and Bioanalysis Letters

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ISSN (Print): 2949-6810
ISSN (Online): 2949-6829

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Letter Article

Stimulatory and Inhibitory Effects of Steroid Hormones and Human Cytochrome P450 (CYP) 3A Inhibitors on Cortisol 6β-Hydroxylation Catalyzed by CYP3A Subfamilies

Author(s): Toshiro Niwa*, Misaki Tani, Anna Suzuki and Mizuho Murakami

Volume 16, Issue 2, 2023

Published on: 09 October, 2023

Page: [73 - 80] Pages: 8

DOI: 10.2174/2949681016666230830125358

Price: $65

Abstract

Objective: The inhibitory and stimulatory effects of several compounds, including steroid hormones and azole antifungal agents, on cortisol 6β-hydroxylation activity by cytochrome P450 (CYP) 3A4, polymorphically expressed CYP3A5, and fetal CYP3A7 were compared with those on testosterone 6β-hydroxylation to clarify the catalytic properties of the predominant forms of the human CYP3A subfamily.

Methods: 6β-Hydroxylation activities of cortisol and testosterone by CYP3A4, CYP3A5, and CYP3A7 in the absence or presence of dehydroepiandrosterone (DHEA), α-naphthoflavone (ANF), ketoconazole, itraconazole, and voriconazole were measured using high-performance liquid chromatography.

Results: Lower concentrations of DHEA and ANF increased cortisol 6β-hydroxylation activities catalyzed by CYP3A4 but not those catalyzed by CYP3A5 and CYP3A7. The inhibition strength of azole antifungal agents against cortisol 6β-hydroxylation catalyzed by all CYP3A subfamilies was similar to that of testosterone 6β-hydroxylation. Although the Michaelis constant (Km) increased 2-fold in the presence of 20 μM DHEA compared to that of the control, the maximal velocity (Vmax) values gradually increased with increasing DHEA. For ANF, both Km and Vmax values increased, although the Km value decreased at 2.5 μM concentrations. Ketoconazole and itraconazole competitively inhibited cortisol 6β-hydroxylation mediated by CYP3A4 with similar inhibition constants.

Conclusion: The inhibitory/stimulatory pattern among CYP3A subfamily members differed between cortisol and testosterone, and CYP3A4 was found to be the most sensitive in terms of inhibition by azole antifungals among the CYP3A subfamily members investigated.

« Previous Next »
[1]
Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y.; Guengerich, F.P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: Studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther., 1994, 270(1), 414-423.
[PMID: 8035341]
[2]
Imaoka, S.; Yamada, T.; Hiroi, T.; Hayashi, K.; Sakaki, T.; Yabusaki, Y.; Funae, Y. Multiple forms of human P450 expressed in Saccharomyces cerevisiae. Biochem. Pharmacol., 1996, 51(8), 1041-1050.
[http://dx.doi.org/10.1016/0006-2952(96)00052-4] [PMID: 8866826]
[3]
Williams, J.A.; Hyland, R.; Jones, B.C.; Smith, D.A.; Hurst, S.; Goosen, T.C.; Peterkin, V.; Koup, J.R.; Ball, S.E. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab. Dispos., 2004, 32(11), 1201-1208.
[http://dx.doi.org/10.1124/dmd.104.000794] [PMID: 15304429]
[4]
Kuehl, P.; Zhang, J.; Lin, Y.; Lamba, J.; Assem, M.; Schuetz, J.; Watkins, P.B.; Daly, A.; Wrighton, S.A.; Hall, S.D.; Maurel, P.; Relling, M.; Brimer, C.; Yasuda, K.; Venkataramanan, R.; Strom, S.; Thummel, K.; Boguski, M.S.; Schuetz, E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet., 2001, 27(4), 383-391.
[http://dx.doi.org/10.1038/86882] [PMID: 11279519]
[5]
Kitada, M.; Kamataki, T.; Itahashi, K.; Rikihisa, T.; Kato, R.; Kanakubo, Y. Purification and properties of cytochrome P-450 from homogenates of human fetal livers. Arch. Biochem. Biophys., 1985, 241(1), 275-280.
[http://dx.doi.org/10.1016/0003-9861(85)90383-2] [PMID: 4026319]
[6]
Li, H.; Lampe, J.N. Neonatal cytochrome P450 CYP3A7: A comprehensive review of its role in development, disease, and xenobiotic metabolism. Arch. Biochem. Biophys., 2019, 673, 108078.
[http://dx.doi.org/10.1016/j.abb.2019.108078] [PMID: 31445893]
[7]
Komori, M.; Nishio, K.; Ohi, H.; Kitada, M.; Kamataki, T. Molecular cloning and sequence analysis of cDNA containing the entire coding region for human fetal liver cytochrome P-450. J. Biochem., 1989, 105(2), 161-163.
[http://dx.doi.org/10.1093/oxfordjournals.jbchem.a122632] [PMID: 2722762]
[8]
de Wildt, S.N.; Kearns, G.L.; Leeder, J.S.; van den Anker, J.N. Cytochrome P450 3A. Clin. Pharmacokinet., 1999, 37(6), 485-505.
[http://dx.doi.org/10.2165/00003088-199937060-00004] [PMID: 10628899]
[9]
Daly, A.K. Significance of the minor cytochrome P450 3A isoforms. Clin. Pharmacokinet., 2006, 45(1), 13-31.
[http://dx.doi.org/10.2165/00003088-200645010-00002] [PMID: 16430309]
[10]
Yamazaki, H.; Niwa, T.; Murayama, N.; Emoto, C. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr. Drug Metab., 2008, 9(1), 20-33.
[http://dx.doi.org/10.2174/138920008783331121] [PMID: 18220568]
[11]
Niwa, T.; Murayama, N.; Yamazaki, H. Comparison of the contributions of cytochrome P450 3A4 and 3A5 in drug oxidation rates and substrate inhibition. J. Health Sci., 2010, 56(3), 239-256.
[http://dx.doi.org/10.1248/jhs.56.239]
[12]
Rendic, S. Summary of information on human CYP enzymes: Human P450 metabolism data. Drug Metab. Rev., 2002, 34(1-2), 83-448.
[http://dx.doi.org/10.1081/DMR-120001392] [PMID: 11996015]
[13]
Niwa, T.; Murayama, N.; Imagawa, Y.; Yamazaki, H. Regioselective hydroxylation of steroid hormones by human cytochromes P450. Drug Metab. Rev., 2015, 47(2), 89-110.
[http://dx.doi.org/10.3109/03602532.2015.1011658] [PMID: 25678418]
[14]
U.S. Food and Drug Administration. Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers. 2014. Available from: http://www.fda.gov/Drugs/DevelopmentApproval ProCess/DevelopmentResources/DrugInteractionsLabeling/ucm093 66 4.htm#4
[15]
European Medicines Agency. Guideline on the investigation of drug interactions, 2012. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500129606.pdf#search='European+Medicines+Agency%2C+drug+interaction'
[16]
Pharmaceuticals and Medical Devices Agency. Methods of drug interaction studies (PMSB/ELD Notification No. 813; 4 June, 2001)., 2001. Available from: http://www.nihs.go.jp/phar/pdf/DiGl EngFinal 011209.pdf
[17]
Thau, L.; Gandhi, J.; Sharma, S. Physiology, Cortisol. In: StatPearls; StatPearls Publishing: Treasure Island, FL, 2022.
[18]
Benfield, R.D.; Newton, E.R.; Tanner, C.J.; Heitkemper, M.M. Cortisol as a biomarker of stress in term human labor: Physiological and methodological issues. Biol. Res. Nurs., 2014, 16(1), 64-71.
[http://dx.doi.org/10.1177/1099800412471580] [PMID: 23338011]
[19]
Nakamura, Y.; Walker, B.R.; Ikuta, T. Systematic review and meta-analysis reveals acutely elevated plasma cortisol following fasting but not less severe calorie restriction. Stress, 2016, 19(2), 151-157.
[http://dx.doi.org/10.3109/10253890.2015.1121984] [PMID: 26586092]
[20]
Galteau, M.M.; Shamsa, F. Urinary 6?-hydroxycortisol: A validated test for evaluating drug induction or drug inhibition mediated through CYP3A in humans and in animals. Eur. J. Clin. Pharmacol., 2003, 59(10), 713-733.
[http://dx.doi.org/10.1007/s00228-003-0690-3] [PMID: 14605790]
[21]
Peng, C-C.; Templeton, I.; Thummel, K.E.; Davis, C.; Kunze, K.L.; Isoherranen, N. Evaluation of 6β-hydroxycortisol, 6β-hydroxycor-tisone, and a combination of the two as endogenous probes for inhibition of CYP3A4 in vivo. Clin. Pharmacol. Ther., 2011, 89(6), 888-895.
[http://dx.doi.org/10.1038/clpt.2011.53] [PMID: 21490593]
[22]
Rais, N.; Chawla, Y.K.; Kohli, K.K. CYP3A phenotypes and genotypes in North Indians. Eur. J. Clin. Pharmacol., 2006, 62(6), 417-422.
[http://dx.doi.org/10.1007/s00228-006-0105-3] [PMID: 16758258]
[23]
Kitada, M.; Kamataki, T.; Itahashi, K.; Rikihisa, T.; Kanakubo, Y. P-450 HFLa, a form of cytochrome P-450 purified from human fetal livers, is the 16 α-hydroxylase of dehydroepiandrosterone 3-sulfate. J. Biol. Chem., 1987, 262(28), 13534-13537.
[http://dx.doi.org/10.1016/S0021-9258(19)76460-6] [PMID: 3654629]
[24]
Ohmori, S.; Fujiki, N.; Nakasa, H.; Nakamura, H.; Ishii, I.; Itahashi, K.; Kitada, M. Steroid hydroxylation by human fetal CYP3A7 and human NADPH-cytochrome P450 reductase coexpressed in insect cells using baculovirus. Res. Commun. Mol. Pathol. Pharmacol., 1998, 100(1), 15-28.
[PMID: 9644715]
[25]
Niwa, T.; Narita, K.; Okamoto, A.; Murayama, N.; Yamazaki, H. Comparison of steroid hormone hydroxylations by and docking to human cytochromes P450 3A4 and 3A5. J. Pharm. Pharm. Sci., 2019, 22(1), 332-339.
[http://dx.doi.org/10.18433/jpps30558] [PMID: 31339834]
[26]
Niwa, T.; Okamoto, A.; Narita, K.; Toyota, M.; Kato, K.; Kobayashi, K.; Sasaki, S. Comparison of steroid hormone hydroxylation mediated by cytochrome P450 3A subfamilies. Arch. Biochem. Biophys., 2020, 682, 108283.
[http://dx.doi.org/10.1016/j.abb.2020.108283] [PMID: 32001245]
[27]
Niwa, T.; Shiraga, T.; Yamasaki, S.; Ishibashi, K.; Ohno, Y.; Kagayama, A. In vitro activation of 7-benzyloxyresorufin O -debenzylation and nifedipine oxidation in human liver microsomes. Xenobiotica, 2003, 33(7), 717-729.
[http://dx.doi.org/10.1080/0049825031000121617] [PMID: 12893521]
[28]
Niwa, T.; Murayama, N.; Yamazaki, H. Heterotropic cooperativity in oxidation mediated by cytochrome p450. Curr. Drug Metab., 2008, 9(5), 453-462.
[http://dx.doi.org/10.2174/138920008784746364] [PMID: 18537580]
[29]
Nakamura, H.; Torimoto, N.; Ishii, I.; Ariyoshi, N.; Nakasa, H.; Ohmori, S.; Kitada, M. CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids. Drug Metab. Dispos., 2003, 31(4), 432-438.
[http://dx.doi.org/10.1124/dmd.31.4.432] [PMID: 12642469]
[30]
Niwa, T.; Toyota, M.; Kawasaki, H.; Ishii, R.; Sasaki, S. Comparison of the stimulatory and inhibitory effects of steroid hormones and α-naphthoflavone on steroid hormone hydroxylation catalyzed by human cytochrome P450 3A subfamilies. Biol. Pharm. Bull., 2021, 44(4), 579-584.
[http://dx.doi.org/10.1248/bpb.b20-00987] [PMID: 33790108]
[31]
Domanski, T.L.; He, Y.A.; Harlow, G.R.; Halpert, J.R. Dual role of human cytochrome P450 3A4 residue Phe-304 in substrate specificity and cooperativity. J. Pharmacol. Exp. Ther., 2000, 293(2), 585-591.
[PMID: 10773032]
[32]
Hollenberg, P.F. Characteristics and common properties of inhibitors, inducers, and activators of CYP enzymes. Drug Metab. Rev., 2002, 34(1-2), 17-35.
[http://dx.doi.org/10.1081/DMR-120001387] [PMID: 11996009]
[33]
Müller, C.S.; Knehans, T.; Davydov, D.R.; Bounds, P.L.; von Mandach, U.; Halpert, J.R.; Caflisch, A.; Koppenol, W.H. Concurrent cooperativity and substrate inhibition in the epoxidation of carbamazepine by cytochrome P450 3A4 active site mutants inspired by molecular dynamics simulations. Biochemistry, 2015, 54(3), 711-721.
[http://dx.doi.org/10.1021/bi5011656] [PMID: 25545162]
[34]
Hackett, J.C. Membrane-embedded substrate recognition by cytochrome P450 3A4. J. Biol. Chem., 2018, 293(11), 4037-4046.
[http://dx.doi.org/10.1074/jbc.RA117.000961] [PMID: 29382727]
[35]
Balding, P.R.; Porro, C.S.; McLean, K.J.; Sutcliffe, M.J.; Maréchal, J.D.; Munro, A.W.; Visser, S.P. How do azoles inhibit cytochrome P450 enzymes? A density functional study. J. Phys. Chem. A, 2008, 112(50), 12911-12918.
[http://dx.doi.org/10.1021/jp802087w] [PMID: 18563875]
[36]
Niwa, T.; Imagawa, Y.; Yamazaki, H. Drug interactions between nine antifungal agents and drugs metabolized by human cytochromes P450. Curr. Drug Metab., 2015, 15(7), 651-679.
[http://dx.doi.org/10.2174/1389200215666141125121511] [PMID: 25429674]
[37]
Cypex. Human CYPs. 2022. Available from: https://cypex.co.uk/products/human-cyps/
[38]
Niwa, T.; Inoue, S.; Shiraga, T.; Takagi, A. No inhibition of cytochrome P450 activities in human liver microsomes by sulpiride, an antipsychotic drug. Biol. Pharm. Bull., 2005, 28(1), 188-191.
[http://dx.doi.org/10.1248/bpb.28.188] [PMID: 15635191]
[39]
Yamaoka, K.; Tanigawara, Y.; Nakagawa, T.; Uno, T. A pharmacokinetic analysis program (multi) for microcomputer. J. Pharmacobiodyn., 1981, 4(11), 879-885.
[http://dx.doi.org/10.1248/bpb1978.4.879] [PMID: 7328489]
[40]
Park, H.; Lee, S.; Suh, J. Structural and dynamical basis of broad substrate specificity, catalytic mechanism, and inhibition of cytochrome P450 3A4. J. Am. Chem. Soc., 2005, 127(39), 13634-13642.
[http://dx.doi.org/10.1021/ja053809q] [PMID: 16190729]
[41]
Godamudunage, M.P.; Grech, A.M.; Scott, E.E. Comparison of antifungal azole interactions with adult cytochrome P450 3A4 versus neonatal cytochrome P450 3A7. Drug Metab. Dispos., 2018, 46(9), 1329-1337.
[http://dx.doi.org/10.1124/dmd.118.082032] [PMID: 29991575]

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