Abstract
Preclinical safety evaluation with laboratory animals may not accurately predict human drug safety due to species differences in response to toxicants. Here the Human Cell Paradigm, namely, that human-specific drug properties can be obtained with in vitro human-based experimental systems is proposed. The success of the Human Cell Paradigm depends on the physiological relevance of the in vitro system, namely, the retention of human-specific and organ-specific properties. Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent a practical and useful experimental system to assess human-specific hepatic drug properties. In this chapter, the scientific rationale and experimental approaches for the application of primary cultured human hepatocytes to evaluate drug-induced liver injuries (DILI) is reviewed. This review focuses on experimental approaches based on the Key Idiosyncratic Determinant (KID) hypothesis—that drugs with KID are likely to cause idiosyncratic drug toxicity. We have identified that metabolism-dependent toxicity and induction of reactive oxygen species as two important KIDs. In vitro experimental approaches with primary cultured human hepatocytes that can be applied in drug development for optimization and prioritization of chemical structures based on human hepatotoxic potential are described.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Li AP, Zhang J (2016) Editorial: promising approaches to identify DILI drugs. Chem Biol Interact 255:1–2
Lo Re V 3rd, Haynes K, Forde KA, Goldberg DS, Lewis JD, Carbonari DM, Leidl KB, Reddy KR, Nezamzadeh MS, Roy J, Sha D, Marks AR, De Boer J, Schneider JL, Strom BL, Corley DA (2015) Risk of acute liver failure in patients with drug-induced liver injury: evaluation of Hy’s law and a new prognostic model. Clin Gastroenterol Hepatol 13:2360–2368
Suzuki A, Andrade RJ, Bjornsson E, Lucena MI, Lee WM, Yuen NA, Hunt CM, Freston JW (2010) Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work. Drug Saf 33:503–522
Watkins PB (2005) Idiosyncratic liver injury: challenges and approaches. Toxicol Pathol 33:1–5
Hussaini SH, Farrington EA (2014) Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert Opin Drug Saf 13:67–81
Li AP (2004) In vitro approaches to evaluate ADMET drug properties. Curr Top Med Chem 4:701–706
Di L, Atkinson K, Orozco CC, Funk C, Zhang H, McDonald TS, Tan B, Lin J, Chang C, Obach RS (2013) In vitro-in vivo correlation for low-clearance compounds using hepatocyte relay method. Drug Metab Dispos 41:2018–2023
Wohlfarth A, Scheidweiler KB, Pang S, Zhu M, Castaneto M, Kronstrand R, Huestis MA (2016) Metabolic characterization of AH-7921, a synthetic opioid designer drug: in vitro metabolic stability assessment and metabolite identification, evaluation of in silico prediction, and in vivo confirmation. Drug Test Anal 8:779–791
Li AP (2010) Evaluation of drug metabolism, drug-drug interactions, and in vitro hepatotoxicity with cryopreserved human hepatocytes. Methods Mol Biol 640:281–294
Li AP (2014) In vitro human hepatocyte-based experimental systems for the evaluation of human drug metabolism, drug-drug interactions, and drug toxicity in drug development. Curr Top Med Chem 14:1325–1338
Funk C, Roth A (2017) Current limitations and future opportunities for prediction of DILI from in vitro. Arch Toxicol 91:131–142
Li AP (2004) Accurate prediction of human drug toxicity: a major challenge in drug development. Chem Biol Interact 150:3–7
Baillie TA, Rettie AE (2011) Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism. Drug Metab Pharmacokinet 26:15–29
Ho MD, Ring N, Amaral K, Doshi U, Li AP (2017) Human enterocytes as an in vitro model for the evaluation of intestinal drug metabolism: characterization of drug-metabolizing enzyme activities of cryopreserved human enterocytes from twenty-four donors. Drug Metab Dispos 45:686–691
von Richter O, Burk O, Fromm MF, Thon KP, Eichelbaum M, Kivisto KT (2004) Cytochrome P450 3A4 and P-glycoprotein expression in human small intestinal enterocytes and hepatocytes: a comparative analysis in paired tissue specimens. Clin Pharmacol Ther 75:172–183
Somers GI, Lindsay N, Lowdon BM, Jones AE, Freathy C, Ho S, Woodrooffe AJ, Bayliss MK, Manchee GR (2007) A comparison of the expression and metabolizing activities of phase I and II enzymes in freshly isolated human lung parenchymal cells and cryopreserved human hepatocytes. Drug Metab Dispos 35:1797–1805
Dixon J, Lane K, Macphee I, Philips B (2014) Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism. Int J Mol Sci 15:2538–2553
Easterbrook J, Fackett D, Li AP (2001) A comparison of aroclor 1254-induced and uninduced rat liver microsomes to human liver microsomes in phenytoin O-deethylation, coumarin 7-hydroxylation, tolbutamide 4-hydroxylation, S-mephenytoin 4′-hydroxylation, chloroxazone 6-hydroxylation and testosterone 6beta-hydroxylation. Chem Biol Interact 134:243–249
Lee K, Vandenberghe Y, Herin M, Cavalier R, Beck D, Li A, Verbeke N, Lesne M, Roba J (1994) Comparative metabolism of SC-42867 and SC-51089, two PGE2 antagonists, in rat and human hepatocyte cultures. Xenobiotica 24:25–36
Li AP (2007) Human-based in vitro experimental systems for the evaluation of human drug safety. Curr Drug Saf 2:193–199
Li AP (2015) Evaluation of adverse drug properties with cryopreserved human hepatocytes and the integrated discrete multiple organ co-culture (IdMOC(TM)) system. Toxicol Res 31:137–149
Loretz LJ, Li AP, Flye MW, Wilson AG (1989) Optimization of cryopreservation procedures for rat and human hepatocytes. Xenobiotica 19:489–498
Li AP, Lu C, Brent JA, Pham C, Fackett A, Ruegg CE, Silber PM (1999) Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. Chem Biol Interact 121:17–35
Li AP (2007) Human hepatocytes: isolation, cryopreservation and applications in drug development. Chem Biol Interact 168:16–29
Nicoletti P, Werk AN, Sawle A, Shen Y, Urban TJ, Coulthard SA, Bjornsson ES, Cascorbi I, Floratos A, Stammschulte T, Gundert-Remy U, Nelson MR, Aithal GP, Daly AK (2016) HLA-DRB1*16: 01-DQB1*05: 02 is a novel genetic risk factor for flupirtine-induced liver injury. Pharmacogenet Genomics 26:218–224
Daly AK, Donaldson PT, Bhatnagar P, Shen Y, Pe'er I, Floratos A, Daly MJ, Goldstein DB, John S, Nelson MR, Graham J, Park BK, Dillon JF, Bernal W, Cordell HJ, Pirmohamed M, Aithal GP, Day CP (2009) HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 41:816–819
Nicoletti P, Aithal GP, Bjornsson ES, Andrade RJ, Sawle A, Arrese M, Barnhart HX, Bondon-Guitton E, Hayashi PH, Bessone F, Carvajal A, Cascorbi I, Cirulli ET, Chalasani N, Conforti A, Coulthard SA, Daly MJ, Day CP, Dillon JF, Fontana RJ, Grove JI, Hallberg P, Hernandez N, Ibanez L, Kullak-Ublick GA, Laitinen T, Larrey D, Lucena MI, Maitland-van der Zee AH, Martin JH, Molokhia M, Pirmohamed M, Powell EE, Qin S, Serrano J, Stephens C, Stolz A, Wadelius M, Watkins PB, Floratos A, Shen Y, Nelson MR, Urban TJ, Daly AK (2017) Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study. Gastroenterology 152:1078–1089
Jiang J, Zhang X, Huo R, Li X, Yang Y, Gai Z, Xu M, Shen L, Cai L, Wan C, Li B, He L, Qin S (2015) Association study of UGT1A9 promoter polymorphisms with DILI based on systematically regional variation screen in Chinese population. Pharmacogenomics J 15:326–331
Li AP (2002) A review of the common properties of drugs with idiosyncratic hepatotoxicity and the “multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 142:7–23
Zhang J, Doshi U, Suzuki A, Chang CW, Borlak J, Li AP, Tong W (2016) Evaluation of multiple mechanism-based toxicity endpoints in primary cultured human hepatocytes for the identification of drugs with clinical hepatotoxicity: results from 152 marketed drugs with known liver injury profiles. Chem Biol Interact 255:3–11
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J (2008) Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 135:1924–1934.e4
Mindikoglu AL, Magder LS, Regev A (2009) Outcome of liver transplantation for drug-induced acute liver failure in the United States: analysis of the united network for organ sharing database. Liver Transpl 15:719–729
Reuben A, Koch DG, Lee WM (2010) Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 52:2065–2076
Gomez-Lechon MJ, Donato MT, Castell JV, Jover R (2003) Human hepatocytes as a tool for studying toxicity and drug metabolism. Curr Drug Metab 4:292–312
Li AP (2009) Metabolism comparative cytotoxicity assay (MCCA) and cytotoxic metabolic pathway identification assay (CMPIA) with cryopreserved human hepatocytes for the evaluation of metabolism-based cytotoxicity in vitro: proof-of-concept study with aflatoxin B1. Chem Biol Interact 179:4–8
Yucha RW, He K, Shi Q, Cai L, Nakashita Y, Xia CQ, Liao M (2017) In vitro drug-induced liver injury prediction: criteria optimization of efflux transporter IC50 and physicochemical properties. Toxicol Sci 157:487–499
Guo YX, Xu XF, Zhang QZ, Li C, Deng Y, Jiang P, He LY, Peng WX (2015) The inhibition of hepatic bile acids transporters Ntcp and Bsep is involved in the pathogenesis of isoniazid/rifampicin-induced hepatotoxicity. Toxicol Mech Methods 25:382–387
Kozlov AV, Lancaster JR Jr, Meszaros AT, Weidinger A (2017) Mitochondria-meditated pathways of organ failure upon inflammation. Redox Biol 13:170–181
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Li, A.P. (2018). Evaluation of Drug-Induced Liver Injuries (DILI) with Human Hepatocytes: Scientific Rationale and Experimental Approaches. In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-7677-5_9
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7677-5_9
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-4939-7676-8
Online ISBN: 978-1-4939-7677-5
eBook Packages: Springer Protocols