Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity

Shuai Zhang; Tingting Wang; Ye Feng; Fei Li; Aijuan Qu; Xiuchen Guan; Hui Wang; Dan Xu

doi:10.1016/j.jpha.2023.07.013

Volume 13 Issue 12

Dec. 2023

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(12): 1510-1525

Shuai Zhang, Tingting Wang, Ye Feng, Fei Li, Aijuan Qu, Xiuchen Guan, Hui Wang, Dan Xu. Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity[J]. Journal of Pharmaceutical Analysis, 2023, 13(12): 1510-1525. doi: 10.1016/j.jpha.2023.07.013

Citation:

Shuai Zhang, Tingting Wang, Ye Feng, Fei Li, Aijuan Qu, Xiuchen Guan, Hui Wang, Dan Xu. Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity[J]. Journal of Pharmaceutical Analysis, 2023, 13(12): 1510-1525. doi: 10.1016/j.jpha.2023.07.013

Citation:

Shuai Zhang, Tingting Wang, Ye Feng, Fei Li, Aijuan Qu, Xiuchen Guan, Hui Wang, Dan Xu. Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity[J]. Journal of Pharmaceutical Analysis, 2023, 13(12): 1510-1525. doi: 10.1016/j.jpha.2023.07.013

PDF( 7699 KB)

Pregnenolone 16α-carbonitrile negatively regulates hippocampal cytochrome P450 enzymes and ameliorates phenytoin-induced hippocampal neurotoxicity

doi: 10.1016/j.jpha.2023.07.013

Shuai Zhang^a,c,
Tingting Wang^a,c,
Ye Feng^d,
Fei Li^e,
Aijuan Qu^f,g,
Xiuchen Guan^h,
Hui Wang^{b,c
,
,},
Dan Xu^{a,c
,
,}

a. Department of Obstetric, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China;
b. Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, China;
c. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan University, Wuhan, 430071, China;
d. Department of Endocrinology and Metabolic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China;
e. Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China;
f. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China;
g. Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing, 100069, China;
h. Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, 100069, China

Funds:

This work was supported in part by grants from the National Natural Science Foundation of China (Grant Nos.: 81973405, 82122071, and 82030111) to Dan Xu and Hui Wang, the National Key R&

D Program of China (Grant No.: 2020YFA0803900) to Hui Wang, and the Hubei Provincial Natural Science Foundation Outstanding Youth Found, China (Grant No.: 2022CFA083).

Received Date: Dec. 14, 2022
Accepted Date: Jul. 19, 2023
Rev Recd Date: Jul. 18, 2023
Publish Date: Jul. 25, 2023

Abstract

Abstract

The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in the metabolism of neurosteroids. The antiepileptic drug phenytoin (PHT) has been observed to induce neuronal side effects in patients, which could be attributed to its induction of CYP expression and testosterone (TES) metabolism in the hippocampus. While pregnane X receptor (PXR) is widely known for its regulatory function of CYPs in the liver, we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, has differential effects on CYP expression in the liver and hippocampus. Specifically, the PCN treatment resulted in the induction of cytochrome P450, family 3, subfamily a, polypeptide 11 (CYP3A11), and CYP2B10 expression in the liver, while suppressing their expression in the hippocampus. Functionally, the PCN treatment protected mice from PHT-induced hippocampal nerve injury, which was accompanied by the inhibition of TES metabolism in the hippocampus. Mechanistically, we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent, rather than PXR independent, as demonstrated by genetic and pharmacological models. In conclusion, our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR. Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.
- Pregnenolone 16α-carbonitrile,
- Pregnane X receptor,
- Hippocampus,
- Glucocorticoid receptor,
- Phenytoin sodium,
- Neurotoxicity

FullText(HTML)

References(48)

References

[1]	P. Anzenbacher, E. Anzenbacherova, Cytochromes P450 and metabolism of xenobiotics, Cell. Mol. Life Sci. 58 (2001) 737-747.
[2]	W. Kuban, W.A. Daniel, Cytochrome P450 expression and regulation in the brain, Drug Metab. Rev. 53 (2021) 1-29.
[3]	B. Schilter, C.J. Omiecinski, Regional distribution and expression modulation of cytochrome P-450 and epoxide hydrolase mRNAs in the rat brain, Mol. Pharmacol. 44 (1993) 990-996.
[4]	S.L. Miksys, R.F. Tyndale, Drug-metabolizing cytochrome P450s in the brain, J. Psychiatry Neurosci. 27 (2002) 406-415.
[5]	A.G. Herzo, L.A. Levesque, F.W. Drislane, et al., Phenytoin-induced elevation of serum estradiol and reproductive dysfunction in men with epilepsy, Epilepsia 32 (1991) 550-553.
[6]	J.I.T. Isojarvi, E. Tauboell, A.G. Herzog, Effect of antiepileptic drugs on reproductive endocrine function in individuals with epilepsy, CNS Drugs 19 (2005) 207-223.
[7]	A. Quartier, L. Chatrousse, C. Redin, et al., Genes and pathways regulated by androgens in human neural cells, potential candidates for the male excess in autism spectrum disorder, Biol. Psychiatry 84 (2018) 239-252.
[8]	M.I. Ransome, W.C. Boon, Testosterone-induced adult neurosphere growth is mediated by sexually-dimorphic aromatase expression, Front. Cell. Neurosci. 9 (2015), 253.
[9]	M.D. Spritzer, L.A.M. Galea, Testosterone and dihydrotestosterone, but not estradiol, enhance survival of new hippocampal neurons in adult male rats, Dev. Neurobiol. 67 (2007) 1321-1333.
[10]	T.S. Benice, J. Raber, Castration and training in a spatial task alter the number of immature neurons in the hippocampus of male mice, Brain Res. 1329 (2010) 21-29.
[11]	G. Corona, F. Guaraldi, G. Rastrelli, et al., Testosterone deficiency and risk of cognitive disorders in aging males, World J. Mens Health. 39 (2021) 9-18.
[12]	F. Kurth, E. Luders, N.L. Sicotte, et al., Neuroprotective effects of testosterone treatment in men with multiple sclerosis, Neuroimage Clin. 4 (2014) 454-460.
[13]	H. Wang, S. Faucette, R. Moore, et al., Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin, J. Biol. Chem. 279 (2004) 29295-29301.
[14]	J.P. Jackson, S.S. Ferguson, R. Moore, et al., The constitutive active/androstane receptor regulates phenytoin induction of Cyp2c29, Mol. Pharmacol. 65 (2004) 1397-1404.
[15]	P. Torres-Vergara, Y.S. Ho, F. Espinoza, et al., The constitutive androstane receptor and pregnane X receptor in the brain, Br. J. Pharmacol. 177 (2020) 2666-2682.
[16]	W. Xie, J.L. Barwick, M. Downes, et al., Humanized xenobiotic response in mice expressing nuclear receptor SXR, Nature 406 (2000) 435-439.
[17]	C.D. Applegate, G.M. Samoriski, K. Ozduman, Effects of valproate, phenytoin, and MK-801 in a novel model of epileptogenesis, Epilepsia 38 (1997) 631-636.
[18]	S. Sudha, M.K. Lakshmana, N. Pradhan, Chronic phenytoin induced impairment of learning and memory with associated changes in brain acetylcholine esterase activity and monoamine levels, Pharmacol. Biochem. Behav. 52 (1995) 119-124.
[19]	A. Mohan, K. Krishna, Memory impairment allied to temporal lobe epilepsy and its deterioration by phenytoin: A highlight on ameliorative effects of levetiracetam in mouse model, Int. J. Epilepsy 5 (2018) 19-27.
[20]	V. Zoufal, S. Mairinger, M. Brackhan, et al., Imaging P-glycoprotein induction at the blood-brain barrier of a β-amyloidosis mouse model with 11C-metoclopramide PET, J. Nucl. Med. 61 (2020) 1050-1057.
[21]	B. Bauer, A.M. Hartz, G. Fricker, et al., Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood-brain barrier, Mol. Pharmacol. 66 (2004) 413-419.
[22]	T. Yilmaz, M. Akca, Y. Turan, et al., Efficacy of dexamethasone on penicillin-induced epileptiform activity in rats: An electrophysiological study, Brain Res. 1554 (2014) 67-72.
[23]	Y. Zhang, W. Hu, B. Zhang, et al., Ginsenoside Rg1 protects against neuronal degeneration induced by chronic dexamethasone treatment by inhibiting NLRP-1 inflammasomes in mice, Int. J. Mol. Med. 40 (2017) 1134-1142.
[24]	B.W. Peeters, J.A. Tonnaer, M.B. Groen, et al., Glucocorticoid receptor antagonists: New tools to investigate disorders characterized by cortisol hypersecretion, Stress 7 (2004) 233-241.
[25]	J. Shu, G. Qiu, I. Mohammad, A semi-automatic image analysis tool for biomarker detection in immunohistochemistry analysis, 2013 Seventh International Conference on Image and Graphics. July 26-28, 2013, Qingdao, China. IEEE, 2013, 937-942.
[26]	A.T.M. Konkle, M.M. McCarthy, Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain, Endocrinology 152 (2011) 223-235.
[27]	B.N. DuBois, F. Amirrad, R. Mehvar, A comparison of calcium aggregation and ultracentrifugation methods for the preparation of rat brain microsomes for drug metabolism studies, Pharmacology 106 (2021) 687-692.
[28]	P.M. Jeavons, Letter: Behavioural effects of anti-epileptic drugs, Dev. Med. Child Neurol. 18 (1976), 394.
[29]	R.P. Meyer, C.E. Hagemeyer, R. Knoth, et al., Anti-epileptic drug phenytoin enhances androgen metabolism and androgen receptor expression in murine hippocampus, J. Neurochem. 96 (2006) 460-472.
[30]	C. Ghosh, M. Hossain, A. Spriggs, et al., Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: An in vitro study, Epilepsia 56 (2015) 439-449.
[31]	T. Niwa, N. Murayama, Y. Imagawa, et al., Regioselective hydroxylation of steroid hormones by human cytochromes P450, Drug Metab. Rev. 47 (2015) 89-110.
[32]	Y.-Q. Ping, C. Mao, P. Xiao, et al., Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex, Nature 589 (2021) 620-626.
[33]	C. Kara, A. Ucakturk, O.F. Aydin, et al., Adverse effect of phenytoin on glucocorticoid replacement in a child with adrenal insufficiency, J. Pediatr. Endocrinol. Metab. 23 (2010) 963-966.
[34]	J.B. Chalk, K. Ridgeway, T. Brophy, et al., Phenytoin impairs the bioavailability of dexamethasone in neurological and neurosurgical patients, J. Neurol. Neurosurg. Psychiatry 47 (1984) 1087-1090.
[35]	W. Jubiz, A.W. Meikle, Alterations of glucocorticoid actions by other drugs and disease states, Drugs 18 (1979) 113-121.
[36]	S.R. Hunter, A. Vonk, A.K. Mullen Grey, et al., Role of glucocorticoid receptor and pregnane X receptor in dexamethasone induction of rat hepatic aryl hydrocarbon receptor nuclear translocator and NADPH-cytochrome P450 oxidoreductase, Drug. Metab. Dispos. 45 (2017) 118-129.
[37]	E. Haberlandt, C. Weger, S.B. Sigl, et al., Adrenocorticotropic hormone versus pulsatile dexamethasone in the treatment of infantile epilepsy syndromes, Pediatr. Neurol. 42 (2010) 21-27.
[38]	S. Shorvon, M. Ferlisi, The treatment of super-refractory status epilepticus: A critical review of available therapies and a clinical treatment protocol, Brain 134 (2011) 2802-2818.
[39]	K. Thelen, J.B. Dressman, Cytochrome P450-mediated metabolism in the human gut wall, J. Pharm. Pharmacol. 61 (2009) 541-558.
[40]	A.M. Kanner, M.M. Bicchi, Antiseizure medications for adults with epilepsy: A review, JAMA 327 (2022) 1269-1281.
[41]	J. Patocka, Q. Wu, E. Nepovimova, et al., Phenytoin - An anti-seizure drug: overview of its chemistry, pharmacology and toxicology, Food. Chem. Toxicol. 142 (2020), 111393.
[42]	J.D. Cardoso-Vera, L.M. Gomez-Olivan, H. Islas-Flores, et al., Multi-biomarker approach to evaluate the neurotoxic effects of environmentally relevant concentrations of phenytoin on adult zebrafish Danio rerio, Sci. Total Environ. 834 (2022), 155359.
[43]	M.M. Nagib, M.G. Tadros, R.M. Rahmo, et al., Ameliorative effects of α-tocopherol and/or coenzyme Q10 on phenytoin-induced cognitive impairment in rats: role of VEGF and BDNF-TrkB-CREB pathway, Neurotox. Res. 35 (2019) 451-462.
[44]	B.S. McEwen, How do sex and stress hormones affect nerve cells? Ann. N. Y. Acad. Sci. 743 (1994) 1-18.
[45]	A.G. Herzog, K.M. Fowler, Sexual hormones and epilepsy: threat and opportunities, Curr. Opin. Neurol. 18 (2005) 167-172.
[46]	C.A. Frye, Role of androgens in epilepsy, Expert Rev. Neurother. 6 (2006) 1061-1075.
[47]	N. Killer, M. Hock, M. Gehlhaus, et al., Modulation of androgen and estrogen receptor expression by antiepileptic drugs and steroids in hippocampus of patients with temporal lobe epilepsy, Epilepsia 50 (2009) 1875-1890.
[48]	E.G. Schuetz, W. Schmid, G. Schutz, et al., The glucocorticoid receptor is essential for induction of cytochrome P-4502B by steroids but not for drug or steroid induction of CYP3A or P-450 reductase in mouse liver, Drug Metab. Dispos. 28 (2000) 268-278.