Definition
Liver microsomes are a subcellular fraction consisting of vesicles of the endoplasmic reticulum, prepared by liver homogenization and differential centrifugation of the tissue. They are commonly used to investigate hepatic drug metabolism.
The liver is the predominant site of metabolism in the body for a large proportion of pharmaceutical drugs. The rate of metabolism influences the body’s exposure to a drug and can consequently impact the drug’s efficacy and toxicity. Hepatocytes are the major cell type, accounting for approximately 80% of the liver’s mass [1] (see entry “Drug Metabolism Assessment: Hepatocytes”). They express a broad range of enzymes capable of metabolizing xenobiotics and endogenous molecules. The endoplasmic reticulum, a continuous membrane network within the cytosol, is particularly abundant in hepatocytes [2]. A number of key metabolic enzymes are localized to this subcellular organelle, including cytochrome P450 (CYP) and uridine...
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References
Gao B, Jeong W-I, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2007;47(2):729–36. Available from: https://doi.org/10.1002/hep.22034
Csala M, Bánhegyi G, Benedetti A. Endoplasmic reticulum: A metabolic compartment. FEBS Lett. 2006;580(9):2160–5. https://doi.org/10.1016/j.febslet.2006.03.050.
Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. 4th ed. New York: Garland Science; 2002. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26841/
Palade GE, Siekevitz P. Liver microsomes: an integrated morphological and biochemical study. J Biophys Biochem Cytol. 1956;2(2):171–200. https://doi.org/10.1083/jcb.2.2.171.
Pearce RE, et al. Effects of freezing, thawing, and storing human liver microsomes on cytochrome P450 activity. Arch Biochem Biophys. 1996;2:145–69. https://doi.org/10.1006/abbi.1996.0294.
de Duve C. Tissue fraction-past and present. J Cell Biol. 1971;50(1):20d–55d.
Nelson AC, Huang W, Moody DE. Variables in human liver microsome preparation: impact on the kinetics of L-α-Acetylmethadol (LAAM)N-demethylation and dextromethorphan O-demethylation. Drug Metab Dispos. 2001;29(3):319–25.
Lowry OH, et al. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.
Guengerich FP, Martin MV, Sohl CD, Cheng Q. Measurement of cytochrome P450 and NADPH-cytochrome P450 reductase. Nat Protoc. 2009;4(9):1245–51. https://doi.org/10.1038/nprot.2009.121.
Omura T, Sato R. The carbon monoxide-binding pigment of liver microsomes. J Biol Chem. 1954;239(7):2379–85.
Gan L, von Moltke LL, Trepanier LA, Harmatz JS, Greenblatt DJ, Court MH. Role of NADPH-cytochrome P450 reductase and cytochrome-b5/NADH-b5 reductase in variability of CYP3A activity in human liver microsomes. Drug Metab Dispos. 2009;37(1):90–6. https://doi.org/10.1124/dmd.108.023424.
Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004;199(3):193–209. https://doi.org/10.1016/j.taap.2004.01.010.
Zhang H, Gao N, Tian X, Liu T, Fang Y, Zhou J, et al. Content and activity of human liver microsomal protein and prediction of individual hepatic clearance in vivo. Sci Rep. 2015;5:17671. https://doi.org/10.1038/srep17671.
Williams JA, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCI/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201–8. https://doi.org/10.1124/dmd.104.000794.
Houston JB. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem Pharmacol. 1994;47(9):1469–79. https://doi.org/10.1016/0006-2952(94)90520-7.
McGinnity DF, Riley RJ. Predicting drug pharmacokinetics in humans from in vitro metabolism studies. Biochem Soc Trans. 2001;29(2):135–9. https://doi.org/10.1042/bst0290135.
Lee J-Y, Lee SY, Lee K, Oh SJ, Kim SK. Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM–IDA–EPI method. Chem Biol Interact. 2015;229:109–18. https://doi.org/10.1016/j.cbi.2015.01.024.
Di L. Reaction phenoty** to assess victim drug-drug interaction risks. Expert Opin Drug Discov. 2017;12(11):1105–15. https://doi.org/10.1080/17460441.2017.1367280.
Lapham K, Callegari E, Cianfrogna J, Lin J, Niosi M, Orozco CC, et al. In vitro characterization of Ertugliflozin metabolism by UDP-glucuronosyltransferase and cytochrome P450 enzymes. Drug Metab Dispos. 2020;48(12):1350–63. https://doi.org/10.1124/dmd.120.000171.
Chapron BD, Dinh JC, Toren PC, Gaedigk A, Leeder JS. The respective roles of CYP3A4 and CYP2D6 in the metabolism of Pimozide to established and novel metabolites. Drug Metab Dispos. 2020;48(11):1113–20. https://doi.org/10.1124/dmd.120.000188.
Fowler S, Zhang H. In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug–drug interactions. AAPS J. 2008;10(2):410–24. https://doi.org/10.1208/s12248-008-9042-7.
Kosaka M, Zhang D, Wong S, Yan Z. NADPH-independent inactivation of CYP2B6 and NADPH-dependent inactivation of CYP3A4/5 by PBD: potential implication for assessing covalent modulators for time-dependent inhibition. Drug Metab Dispos. 2020;48(8):655–61. https://doi.org/10.1124/dmd.120.090878.
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Wilcock, J., Ward, L. (2022). Drug Metabolism Assessment: Liver Microsomes. In: Talevi, A. (eds) The ADME Encyclopedia. Springer, Cham. https://doi.org/10.1007/978-3-030-84860-6_144
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