Drug metabolism and cytochrome P-450 (CYPs)
DOI:
https://doi.org/10.15218/zjms.2024.012Keywords:
Cytochrome P450, Disease, Free radical, Hepatocyte, LiverAbstract
Cytochrome p-450 (CYPs) convert xenobiotics, chemicals, and drugs in the liver into intoxic materials that can be easily eliminated in the body. However, these CYPs sometimes mediate fatal diseases by converting drugs (for instance, paracetamol) into toxic substances that cannot be eliminated or excreted quickly from the body and hence cause hepatocyte damage that decreases the function of the liver. This article review aimed to determine the history, nomenclature, family, and subfamily of CYPs and mainly stress cytochrome P450 roles in drug metabolism. Some toxic byproducts induce autoreactive antibodies by binding to the CYPs, which causes further damage to hepatocytes. The most common causes of liver damage are type II autoimmune hepatitis, drinking alcohol, and free radicals, which cause DNA mutations. Another condition that leads to liver damage is the inability of the liver to detoxify the drug, which leads to further damage to the liver. There are some isoforms of CYPs, such as 3A, 1A, and 2C19, that are severely affected when the liver is no longer able to relieve toxic products, but some isoforms of CYPs are less affected during damage to the liver, which includes 2E1, 2D6, and 2C9. There are parameters for the involvement of CYPs in liver disease, depending on the cause of the damage, which is either drugs or alcohol. Thus, further research must be done to know the exact etiology and management of the diseases related to liver damage through CYPs.
Metrics
References
Kaur G, Gupta S, Singh P, Ali V, Kumar V, Verma MJC, et al. Drug-metabolizing enzymes: role in drug resistance in cancer. Clin Transl Oncol 2020; 10:1667–80. DOI: 10.1007/s12094-020-02325-7.
Sahini N, Borlak JJPilr. Recent insights into the molecular pathophysiology of lipid droplet formation in hepatocytes. Prog Lipid Res 2014; 54:86–112. DOI: 10.1016/j.plipres.2014.02.002
Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010; 154(2):103–16. DOI: 10.5507/bp.2010.017.
Wang J, Chen Z, Chen H, Wen YJ. Effect of hydrogen peroxide on Microcystic aeruginosa: Role of cytochromes P450. Total Environ 2018; 626:211–8. DOI: 10.1016/j.scitotenv.2018.01.067.
Ramos-TovarE, Muriel PJ. Free radicals, antioxidants, nuclear factor-E2-related factor- 2 and liver damage. J APPL Toxical 2020; 40(1):151–68. DOI: 10.1002/jat.3880.
Ma B, Bohnert T, Otipoby KL, Tien E, Arefayene M, Bai J, et al. Discovery of BIIB068: a selective, potent, reversible Bruton’s tyrosine kinase inhibitor as an orally efficacious agent for autoimmune diseases. J Med Chem 2020; 63(21):12526–41. DOI: 10.1021/acs.jmedchem.0c00702.
Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 practice guidance and guidelines from the American Association for the Study of Liver Diseases. Hepatology 2020; 72(2):671–722. DOI: 10.1002/hep.31065.
Abdelmegeed MA, Banerjee A, Yoo S-H, Jang S, Gonzalez FJ, Song BJ. Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis. J Hepatol 2012; 57(4):860–6. DOI: 10.1016/j.jhep.2012.05.019.
Almazroo OA, Miah MK, Venkataramanan RJCild. Drug metabolism in the liver. Clin Liver Dis 2017; 21(1):1–20. DOI: 10.1016/j.cld.2016.08.001.
Hibi T, Chieh AKW, Chan AC-Y, Bhangui PJIJoS. Current status of liver transplantation in Asia. Int J Surg 2020; 82:4–8. DOI: 10.1016/j.ijsu.2020.05.071.
Lauschke VM, Shafagh RZ, Hendriks DF, Ingelman-Sundberg MJ. 3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism, and toxicity: emerging culture paradigms and applications. Biotech J 2019; 14(7):1800347. DOI: 10.1002/biot.201800347.
Deppermann C, Peiseler M, Zindel J, Zbytnuik L, Lee WY, Pasini E, et al. Tacrolimus impairs Kupffer cell capacity to control bacteremia: Why transplant recipients are susceptible to infection. Hepatology 2021; 73(5):1967–84. DOI: 10.1002/hep.31499.
Omiecinski CJ, Vanden Heuvel JP, Perdew GH, Peters JM. Xenobiotic metabolism, disposition, and regulation by receptors: from biochemical phenomenon to predictors of major toxicities. Toxicol Sci 2011; 120 Suppl 1:S49–75. DOI: 10.1093/toxsci/kfq338.
Wang L, Xu W, Ma L, Zhang S, Zhang K, Ye P, et al. Detoxification of benzo [a] pyrene primarily depends on cytochrome P450, while bioactivation involves additional oxidoreductases including 5-lipoxygenase, cyclooxygenase, and aldo-keto reductase in the liver. J Biochem Molec Toxic 2017; 31(7):e21902. DOI: 10.1002/jbt.21902
Guengerich FPJ. A history of the roles of cytochrome P450 enzymes in the toxicity of drugs. Toxical Res J 2020; 1–23. DOI: 10.1007/s43188-020-00056-z.
Bathe U, Tissier AJP. Cytochrome P450 enzymes: A driving force of plant diterpene diversity. J Phytochemistry 2019;161:149–62. DOI: 10.1016/j.phytochem.2018.12.003.
Kletzin A, Heimerl T, Flechsler J, van Niftrik L, Rachel R, Klingl AJ. Cytochromes c in Archaea: distribution, maturation, cell architecture, and the special case of Ignicoccus hospitalis. Front Microbiol 2015; 6:439. DOI: 10.3389/fmicb.2015.00439.
Go R-E, Hwang K-A, Choi K-C. Cytochrome P450 cancers. J Steroid Biochem Mol Biol 2015; 147:24–30. DOI: 10.1016/j.jsbmb.2014.11.003
Park H, Park G, Jeon W, Ahn J-O, Yang Y-H, Choi K-YJ. Whole-cell biocatalysis using cytochrome P450 monooxygenases for biotransformation of sustainable bioresources (fatty acids, fatty alkanes, and aromatic amino acids). Bitechnol Advan 2020; 40:107504. DOI: 10.1016/j.biotechadv.2020.107504.
Finnigan JD, Young C, Cook DJ, Charnock SJ, Black GW. Cytochromes P450 (P450s): a review of the class system with a focus on prokaryotic P450s. Adv Protein Chem Struct Biol 2020; 122:289–320. DOI: 10.1016/bs.apcsb.2020.06.005.
Esteves F, Rueff J, Kranendonk MJ. The central role of cytochrome P450 in xenobiotic metabolism—A brief review on a fascinating enzyme family. J Xenobiot 2021; 11(3):94–114. DOI: 10.3390/jox11030007.
Gaedigk A, Ingelman‐Sundberg M, Miller NA, Leeder JS, Whirl‐Carrillo M, Klein TE, et al. The Pharmacogene Variation (PharmVar) Consortium: incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther 2018; 103(3):399–401. DOI: 10.1002/cpt.910.
Waring RHJ. Cytochrome P450: genotype to phenotype. Xenobiotica 2020; 50(1):9–18. DOI: 10.1080/00498254.2019.1648911.
Zhang Z, Chen M, Zhang L, Zhao QJBP, Toxicology. The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention. BMC Pharmacol Toxicol 2020; 21(1):1. DOI: 10.1186/s40360-019-0378-7.
Hatzade KM, Ghatole AM, Gaidhane PK, Gaidhane MK, Gadekar GP. A facile synthesis of some new pyrimidine-2, 4, 6-triones analogs and their O-β-D-glucosides P-glycoprotein and antioxidant, antimicrobial study,blood–brain barrier, cytochrome p450 enzyme activity prediction. Medic Chem Res 2021; 30:163–81. DOI: 10.1007/s00044-020-02649-7
Shimada C, Xu R, Al-Alem L, Stasenko M, Spriggs DR, Rueda BR. Galectins and Ovarian Cancer. Cancers J 2020; 12(6):1421. DOI: 10.3390/cancers12061421.
Manikandan P, Nagini S. Cytochrome P450 structure, function and clinical significance. Curr Drug Target 2018; 19(1):38–54. DOI: 10.2174/1389450118666170125144557.
Lin CY, Huang Z, Wen W, Wu A, Wang C, Niu L. Enhancing Protein Expression in HEK-293 Cells by Lowering Culture Temperature. PLoS One. PLoS One 2015; 10(4):e0123562. DOI: 10.1371/journal.pone.0123562.
Yang R, Luo Z, Liu Y, Sun M, Zheng L, Chen Y, et al. Drug interactions with angiotensin receptor blockers: role of human cytochromes P450. Curr Drug Metab 2016; 17(7):681–91. DOI: 10.2174/1389200217666160524143843.
Wang C, Becker K, Pfütze S, Kuhnert E, Stadler M, Cox RJ, et al. Investigating the function of cryptic cytochalasan cytochrome P450 monooxygenases using combinatorial biosynthesis. Org Lett 2019; 21(21):8756–60. DOI: 10.1021/acs.orglett.9b03372.
G RE, Hwan KA, Choi KC. Cytochrome P450 1 family and cancers. J Biol 2015; 147:24–31. DOI: 10.1016/j.j2sbmb.2015.11.0003.
Lim SYM, Loo JSE, Alshagga M, Alshawsh MA, Ong CE, Pan YJTR. In vitro and in silico studies of interactions of cathinone with human recombinant cytochrome P450 CYP (1A2), CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2E1, CYP2J2, and CYP3A5. Toxicol Repor 2022; 9:759–68. DOI: 10.1016/j.toxrep.2022.03.040
Guo Y, Lucksiri A, Dickinson GL, Vuppalanchi RK, Hilligoss JK, Hall SD, et al. Quantitative Prediction of CYP3A4- and CYP3A5- Mediated Drug Interactions. Clin Pharmacol Ther 2020; 107(1):246–56. DOI: 10.1002/cpt.1596.
Fekry MI, Xiao Y, Berg JZ, Guengerich FP. A Role for the Orphan Human Cytochrome P450 2S1 in Polyunsaturated Fatty Acid ω-1 Hydroxylation Using an Untargeted Metabolomic Approach. Drug Metab Dispos 2019; 47(11):1325–32. DOI: 10.1124/dmd.119.089086.
Mo H-Y, Wei Q-Y, Zhong Q-H, Zhao X-Y, Guo D, Han J, et al. Cytochrome P450 27C1 Level Dictates Lung Cancer Tumorigenicity and Sensitivity towards Multiple Anticancer Agents and Its Potential Interplay with the IGF-1R/Akt/p53 Signaling Pathway. Int J Mol 2022; 23(14):7853. DOI: 10.3390/ijms23147853.
Shoieb SM, El-Ghiaty MA, Alqahtani MA, El-Kadi AOJP, Mediators OL. Cytochrome P450-derived eicosanoids and inflammation in liver diseases. J Prostaglandins 2020; 147:106400. DOI: 10.1016/j.prostaglandins.2019.106400.
Porceddu M, Buron N, Roussel C, Labbe G, Fromenty B, Borgne-Sanchez AJ. Prediction of liver injury induced by chemicals in human with a multiparametric assay on isolated mouse liver mitochondria. Toxical Sci 2012; 129(2):332–45. DOI: 10.1093/toxsci/kfs197.
Yokoi T, Oda SJARoP, Toxicology. Models of Idiosyncratic Drug-Induced Liver Injury. Annu Rev Pharmacol Toxicol 2021; 61:247–68. DOI: 10.1146/annurev-pharmtox-030220-015007.
Asrani SK, Devarbhavi H, Eaton J, Kamath PSJJoh. Burden of liver diseases in the world. J Heptaol 2019; 70(1):151–71. DOI: 10.1016/j.jhep.2018.09.014.
Goorden S, Buffart TE, Bakker A, Buijs MMJNtvg. Liver disorders in adults: ALT and AST. Ned Tijdschr Geneeskd 2013; 157(43):A6443–A. PMID: 24152362
Fontana RJ, Hayashi PH, Gu J, Reddy KR, Barnhart H, Watkins PB, et al. Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroen 2014; 147(1):96–108. e4. DOI: 10.1053/j.gastro.2014.03.045.
Xie Y, McGill MR, Dorko K, Kumer SC, Schmitt TM, Forster J, et al. Mechanisms of acetaminophen-induced cell death in primary human hepatocytes. Toxicology applied pharmacology. Toxicol Appl Pharmacol 2014; 279(3):266–74. DOI: 10.1016/j.taap.2014.05.010.
Jessurun NT, Wijnen PA, Bast A, van Puijenbroek EP, Bekers O, Drent MJ. Tamsulosin Associated with Interstitial Lung Damage in CYP2D6 Variant Alleles Carriers. Int J Mol Sci 2020; 21(8):2770. DOI: 10.3390/ijms21082770.
Kargar B, Pishvaee MS, Jahani H, Sheu J-B, Review T. Organ transportation and allocation problem under medical uncertainty: A real case study of liver transplantation. Trans Res 2020; 134:101841. DOI: 10.1016/j.tre.2020.101841
Liu J, Ouyang Y, Chen D, Yao B, Lin D, Li Z, et al. Donor and recipient P450 gene polymorphisms influence individual pharmacological effects of tacrolimus in Chinese liver transplantation patients. Int Immunopahrmaco 2018; 57:18–24. DOI: 10.1016/j.intimp.2018.02.005.
Harjumäki R, Pridgeon CS, Ingelman-Sundberg MJIJoMS. CYP2E1 in alcoholic and non-alcoholic liver injury. Roles of ROS, reactive intermediates and lipid overload. Int J Mol Sci 2021; 22(15):8221. DOI: 10.3390/ijms22158221.
Harskamp RE, Teichert M, Lucassen WA, van Weert HC, Lopes RD. Impact of polypharmacy and P-glycoprotein-and CYP3A4-modulating drugs on safety and efficacy of oral anticoagulation therapy in patients with atrial fibrillation. Cradiovas Drugs Ther 2019; 33(5):615–23. DOI: 10.1007/s10557-019-06907-8.
Taylor C, Crosby I, Yip V, Maguire P, Pirmohamed M, Turner RM. A Review of the Important Role of CYP2D6 in Pharmacogenomics. Genes 2020; 11(11):1295. DOI: 10.3390/genes11111295.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Blnd I. Mohammed, Kawa F. Dizaye , Bushra Karem Amin (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The copyright on any article published in Zanco J Med Sci is retained by the author(s) in agreement with the Creative Commons Attribution Non-Commercial ShareAlike License (CC BY-NC-SA 4.0).
