Generic placeholder image

Drug Metabolism Letters

Editor-in-Chief

ISSN (Print): 1872-3128
ISSN (Online): 1874-0758

Research Article

Comparison of Rat and Human Pulmonary Metabolism Using Precision-cut Lung Slices (PCLS)

Author(s): Yildiz Yilmaz*, Gareth Williams, Markus Walles, Nenad Manevski, Stephan Krähenbühl and Gian Camenisch

Volume 13, Issue 1, 2019

Page: [53 - 63] Pages: 11

DOI: 10.2174/1872312812666181022114622

Abstract

Background: Although the liver is the primary organ of drug metabolism, the lungs also contain drug-metabolizing enzymes and may, therefore, contribute to the elimination of drugs. In this investigation, the Precision-cut Lung Slice (PCLS) technique was standardized with the aims of characterizing and comparing rat and human pulmonary drug metabolizing activity.

Method: Due to the limited availability of human lung tissue, standardization of the PCLS method was performed with rat lung tissue. Pulmonary enzymatic activity was found to vary significantly with rat age and rat strain. The Dynamic Organ Culture (DOC) system was superior to well-plates for tissue incubations, while oxygen supply appeared to have a limited impact within the 4h incubation period used here.

Results: The metabolism of a range of phase I and phase II probe substrates was assessed in rat and human lung preparations. Cytochrome P450 (CYP) activity was relatively low in both species, whereas phase II activity appeared to be more significant.

Conclusion: PCLS is a promising tool for the investigation of pulmonary drug metabolism. The data indicates that pulmonary CYP activity is relatively low and that there are significant differences in enzyme activity between rat and human lung.

Keywords: Precision-cut lung slices (PCLS), rat lung metabolism, human lung metabolism, rat and human pulmonary metabolism activity, pulmonary disposition of phase I and phase II drugs, dynamic organ culture system, AFQ056.

Graphical Abstract
[1]
Del Donno, M.; Verduri, A.; Olivieri, D. Air pollution and reversible chronic respiratory diseases. Monaldi Arch. Chest Dis., 2002, 57, 164-166.
[2]
Rau, J.L. The inhalation of drugs: advantages and problems. Respir. Care Clin. N. Am., 2005, 50, 367-382.
[3]
Stone, K.C.; Mercer, R.R.; Gehr, P.; Stockstill, B.; Crapo, J.D. Allometric relationships of cell numbers and size in the mammalian lung. Am. J. Respir. Cell Mol. Biol., 1992, 6, 235-243.
[4]
Zhang, J.Y.; Wang, Y.; Prakash, C. Xenobiotic-metabolizing enzymes in human lung. Curr. Drug Metab., 2006, 7, 939-948.
[5]
Devereux, T.R.; Domin, B.A.; Philpot, R.M. Xenobiotic metabolism by isolated pulmonary cells. Pharmacol. Ther., 1989, 41, 243-256.
[6]
Raunio, H.; Hakkola, J.; Hukkanen, J.; Lassila, A.; Päivärinta, K.; Pelkonen, O.; Anttila, S.; Piipari, R.; Boobis, A.; Edwards, R.J. Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue. Exp. Toxicol. Pathol., 1999, 51, 412-417.
[7]
Hukkanen, J.; Pelkonen, O.; Hakkola, J.; Raunio, H. Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit. Rev. Toxicol., 2002, 32, 391-411.
[8]
Olsson, B.; Bondesson, E.; Borgström, L.; Edsbäcker, S.; Eirefelt, S.; Ekelund, K.; Gustavsson, L.; Hegelund-Myrbäck, T. Pulmonary Drug Metabolism, Clearance, and Absorption. In:Controlled Pulmonary Drug Delivery., Smyth, H.D.C.; Hickey, A.J., Ed.;Springer: New York, NY, . 2011, 21-50.
[9]
Somers, G.I.; Lindsay, N.; Lowdon, B.M.; Jones, A.E.; Freathy, C.; Ho, S.; Woodrooffe, A.J.; Bayliss, M.K.; Manchee, G.R. 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., 2007, 35, 1797-1805.
[10]
Ioannides, C.; Lake, B.G.; Lyubimov, A.V. Precision-Cut Tissue Slices: A Suitable In vitro System for the Study of the Induction of Drug-Metabolizing Enzyme Systems.In: Encyclopedia of Drug Metabolism and Interactions., A.V. Lyubimov, Ed.; John Wiley & Sons, Inc.: Hoboken, NY. 2011, 879-898.
[11]
Umachandran, M.; Ioannides, C. Stability of cytochromes P450 and phase II conjugation systems in precision-cut rat lung slices cultured up to 72 h. Toxicology, 2006, 224, 14-21.
[12]
De Kanter, R.; Olinga, P.; De Jager, M.H.; Merema, M.T.; Meijer, D.K.; Groothius, G.M. Organ slices as an in vitro test system for drug metabolism in human liver, lung and kidney. Toxicol. In Vitro, 1999, 13, 737-744.
[13]
O’Neil, J.J.; Sanford, R.L.; Wasserman, S.; Tierney, D.F. Metabolism in rat lung tissue slices: technical factors. J. Appl. Physiol. Respir. Environ. Exerc.Physiol., 1977, 43, 902-906.
[14]
Nave, R.; Fisher, R.; Zech, K. In vitro metabolism of ciclesonide in human lung and liver precision-cut tissue slices. Biopharm. Drug Dispos., 2006, 27, 197-207.
[15]
Yilmaz, Y.; Umehara, K.; Williams, G.; Faller, T.; Schiller, H.; Walles, M.; Kraehenbuehl, S.; Camenisch, G.; Manevski, N. Assessment of the pulmonary CYP1A1 metabolism of mavoglurant (AFQ056) in rat. Xenobiotica, 2017, 48(8), 1-11.
[16]
De Kanter, R.; De Jager, M.; Draaisma, A.; Jurva, J.; Olinga, P.; Meijer, D.; Groothuis, G. Drug-metabolizing activity of human and rat liver, lung, kidney and intestine slices. Xenobiotica, 2002, 32, 349-362.
[17]
Kanter, R.; Monshouwer, M.; Meijer, D.; Groothuis, G. Precision-cut organ slices as a tool to study toxicity and metabolism of xenobiotics with special reference to non-hepatic tissues. Curr. Drug Metab., 2002, 3, 39-59.
[18]
de Graaf, I.A.M.; Koster, H. Cryopreservation of precision-cut tissue slices for application in drug metabolism research. Toxicol. In Vitro, 2003, 17, 1-17.
[19]
Liberati, T.A.; Randle, M.R.; Toth, L.A. In vitro lung slices: a powerful approach for assessment of lung pathophysiology. Expert Rev. Mol. Diagn., 2010, 10, 501-508.
[20]
Walles, M.; Wolf, T.; Jin, Y.; Ritzau, M.; Leuthold, L.A.; Krauser, J.; Gschwind, H.P.; Carcache, D.; Kittelmann, M.; Ocwieja, M.; Ufer, M.; Woessner, R.; Chakraborty, A.; Swart, P. Metabolism and disposition of the metabotropic glutamate receptor 5 antagonist (mGluR5) mavoglurant (AFQ056) in healthy subjects. Drug Metab. Dispos., 2013, 41, 1626-1641.
[21]
Ding, X.; Kaminsky, L.S. Human extrahepatic cytochromes P450: function in xenobiotic metabolism and tissue-selective chemical toxicity in the respiratory and gastrointestinal tracts. Annu. Rev. Pharmacol. Toxicol., 2003, 43, 149-173.
[22]
Nishimura, M.; Naito, S. Tissue-specific mRNA expression profiles of human phase I metabolizing enzymes except for cytochrome P450 and phase II metabolizing enzymes. Drug Metab. Pharmacokinet., 2006, 21, 357-374.
[23]
Bieche, I.; Narjoz, C.; Asselah, T.; Vacher, S.; Marcellin, P.; Lidereau, R.; Beaune, P.; de Waziers, I. Reverse transcriptase-PCR quantification of mRNA levels from cytochrome (CYP)1, CYP2 and CYP3 families in 22 different human tissues. Pharmacogenet. Genomics, 2007, 17, 731-742.
[24]
Smith, P.F.; Gandolfi, A.J.; Krumdieck, C.L.; Putnam, C.W.; Zukoski, C.F., III; Davis, W.M.; Brendel, K. Dynamic organ culture of precision liver slices for in vitro toxicology. Life Sci., 1985, 36, 1367-1375.
[25]
Smith, P.F.; Krack, G.; McKee, R.L.; Johnson, D.G.; Gandolfi, A.J.; Hruby, V.J.; Krumdieck, C.L.; Brendel, K. Maintenance of adult rat liver slices in dynamic organ culture. In Vitro Cell. Dev. Biol., 1986, 22, 706-712.
[26]
Sanderson, M.J. Exploring lung physiology in health and disease with lung slices. Pulm. Pharmacol. Ther., 2011, 24, 452-465.
[27]
Dogterom, P. Development of a simple incubation system for metabolism studies with precision-cut liver slices. Drug Metab. Dispos., 1993, 21, 699-704.
[28]
Manevski, N.; Troberg, J.; Svaluto-Moreolo, P.; Dziedzic, K.; Yli-Kauhaluoma, J.; Finel, M. Albumin stimulates the activity of the human UDP-glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the effects are enzyme and substrate dependent. PLoS One, 2013, 8, e54767.
[29]
Wang, L.Q.; Falany, C.N.; James, M.O. Triclosan as a substrate and inhibitor of 3′-phosphoadenosine 5′-phosphosulfate-sulfotransferase and UDP-glucuronosyl transferase in human liver fractions. Drug Metab. Dispos., 2004, 32, 1162-1169.
[30]
Gotz, C.; Pfeiffer, R.; Tigges, J.; Blatz, V.; Jackh, C.; Freytag, E.M.; Fabian, E.; Landsiedel, R.; Merk, H.F.; Krutmann, J.; Edwards, R.J.; Pease, C.; Goebel, C.; Hewitt, N.; Fritsche, E. Xenobiotic metabolism capacities of human skin in comparison with a 3D epidermis model and keratinocyte-based cell culture as in vitro alternatives for chemical testing: activating enzymes (Phase I). Exp. Dermatol., 2012, 21, 358-363.
[31]
Manevski, N.; Swart, P.; Balavenkatraman, K.K.; Bertschi, B.; Camenisch, G.; Kretz, O.; Schiller, H.; Walles, M.; Ling, B.; Wettstein, R.; Schaefer, D.J.; Itin, P.; Ashton-Chess, J.; Pognan, F.; Wolf, A.; Litherland, K. Phase II metabolism in human skin: skin explants show full coverage for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Drug Metab. Dispos., 2015, 43, 126-139.
[32]
Yuan, R.; Madani, S.; Wei, X.X.; Reynolds, K.; Huang, S.M. Evaluation of cytochrome P450 probe substrates commonly used by the pharmaceutical industry to study in vitro drug interactions. Drug Metab. Dispos., 2002, 30, 1311-1319.
[33]
Khan, K.K.; He, Y.Q.; Domanski, T.L.; Halpert, J.R. Midazolam oxidation by cytochrome P450 3A4 and active-site mutants: an evaluation of multiple binding sites and of the metabolic pathway that leads to enzyme inactivation. Mol. Pharmacol., 2002, 61, 495-506.
[34]
Li, X.Q.; Bjorkman, A.; Andersson, T.B.; Ridderstrom, M.; Masimirembwa, C.M. Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J. Pharmacol. Exp. Ther., 2002, 300, 399-407.
[35]
Ono, S.; Hatanaka, T.; Miyazawa, S.; Tsutsui, M.; Aoyama, T.; Gonzalez, F.J.; Satoh, T. Human liver microsomal diazepam metabolism using cDNA-expressed cytochrome P450s: role of CYP2B6, 2C19 and the 3A subfamily. Xenobiotica, 1996, 26, 1155-1166.
[36]
Carlile, D.J.; Hakooz, N.; Bayliss, M.K.; Houston, J.B. Microsomal prediction of in vivo clearance of CYP2C9 substrates in humans. Br. J. Clin. Pharmacol., 1999, 47, 625-635.
[37]
Martignoni, M.; Groothuis, G.M.; de Kanter, R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin. Drug Metab. Toxicol., 2006, 2, 875-894.
[38]
Lang, D.H.; Rettie, A.E. In vitro evaluation of potential in vivo probes for human flavin-containing monooxygenase (FMO): metabolism of benzydamine and caffeine by FMO and P450 isoforms. Br. J. Clin. Pharmacol., 2000, 50, 311-314.
[39]
Yilmaz, Y.; Williams, G.; Manevski, N.; Walles, M.; Krahenbuhl, S.; Camenisch, G. Functional assessment of rat pulmonary flavin-containing monooxygenase activity. Xenobiotica, 2018, 15, 1-10.
[40]
Kaye, B.; Rance, D.J.; Waring, L. Oxidative metabolism of carbazeran in vitro by liver cytosol of baboon and man. Xenobiotica, 1985, 15, 237-242.
[41]
Hutzler, J.M.; Yang, Y.S.; Albaugh, D.; Fullenwider, C.L.; Schmenk, J.; Fisher, M.B. Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes. Drug Metab. Dispos., 2012, 40, 267-275.
[42]
Hutzler, J.M.; Obach, R.S.; Dalvie, D.; Zientek, M.A. Strategies for a comprehensive understanding of metabolism by aldehyde oxidase. Expert Opin. Drug Metab. Toxicol., 2013, 9, 153-168.
[43]
Thomsen, R.; Rasmussen, H.B.; Linnet, K.; Consortium, I. In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors. Drug Metab. Dispos., 2014, 42, 126-133.
[44]
Linz, W.; Scholkens, B.A.; Kaiser, J.; Just, M.; Qi, B.Y.; Albus, U.; Petry, P. Cardiac arrhythmias are ameliorated by local inhibition of angiotensin formation and bradykinin degradation with the converting-enzyme inhibitor ramipril. Cardiovasc. Drugs Ther., 1989, 3, 873-882.
[45]
Joseph, D.; Puttaswamy, R.K.; Krovvidi, H. Non-respiratory functions of the lung. Contin. Educ. Anaesth. Crit. Care Pain, 2013, 13, 98-102.
[46]
Van Bezooijen, C.F.A.; Horbach, G.J.M.J.; Hollander, C.F. The Effect of Age on Rat Liver Drug Metabolism. In: Drugs and Aging., Platt, D., Ed.; Springer Berlin Heidelberg: Berlin, Heidelberg. 1986, 45-55.
[47]
Bozhkov, A.I.; Nikitchenko, Y.V.; Klimova, E.M.; Linkevych, O.S.; Lebid, K.M.; Al-Bahadli, A.M.M.; Alsardia, M.M.A. Young and old rats have different strategies of metabolic adaptation to Cu-induced liver fibrosis. Adv. Gerontol., 2017, 7, 41-50.
[48]
Yamamoto, Y.; Tanaka, A.; Kanamaru, A.; Tanaka, S.; Tsubone, H.; Atoji, Y.; Suzuki, Y. Morphology of aging lung in F344/N rat: Alveolar size, connective tissue, and smooth muscle cell markers. Anat. Rec. Part A: Discov. Mol. Cell. Evol. Biol., 2003, 272A, 538-547.
[49]
Samuel, J.J.; Nick, A.; Doug, B.; Ilaria, B.; James, G.; Lamia, H.; Alan, H.; Judy, L.; Anja, P.; Paul, P.; Andrew, R.; Alison, R.; Michelle, S.; Carol, S.; Mark, Y.; Kathryn, C. Does age matter? The impact of rodent age on study outcomes. Lab. Anim., 2016, 51, 160-169.
[50]
McCutcheon, J.E.; Marinelli, M. Age matters. Eur. J. Neurosci., 2009, 29, 997-1014.
[51]
Nijjar, M.S.; Ho, J.C. Isolation of plasma membranes from rat lungs: effect of age on the subcellular distribution of adenylate cyclase activity. Biochim. Biophys. Acta, 1980, 600, 238-243.
[52]
Nishiyama, Y.; Nakayama, S.M.; Watanabe, K.P.; Kawai, Y.K.; Ohno, M.; Ikenaka, Y.; Ishizuka, M. Strain differences in cytochrome P450 mRNA and protein expression, and enzymatic activity among Sprague Dawley, Wistar, Brown Norway and Dark Agouti rats. J. Vet. Med. Sci., 2016, 78, 675-680.
[53]
Morin, J.P.; Baste, J.M.; Gay, A.; Crochemore, C.; Corbiere, C.; Monteil, C. Precision cut lung slices as an efficient tool for in vitro lung physio-pharmacotoxicology studies. Xenobiotica, 2013, 43, 63-72.
[54]
Parrish, A.R.; Gandolfi, A.J.; Brendel, K. Precision-cut tissue slices: applications in pharmacology and toxicology. Life Sci., 1995, 57, 1887-1901.
[55]
Fisher, R.L.; Shaughnessy, R.P.; Jenkins, P.M.; Austin, M.L.; Roth, G.L.; Gandolfi, A.J.; Brendel, K. Dynamic organ culture is superior to multiwell plate culture for maintaining precision-cut tissue slices: optimization of tissue slice culture, Part 1. Toxicol. Methods, 1995, 5, 99-113.
[56]
Umachandran, M.; Howarth, J.; Ioannides, C. Metabolic and structural viability of precision-cut rat lung slices in culture. Xenobiotica, 2004, 34, 771-780.
[57]
Monteil, C.; Guerbet, M.; Le Prieur, E.; Morin, J.-P.; Jouany, M Fillastre, J.P., Characterization of precision-cut rat lung slices in a biphasic gas/liquid exposure system: effect of O2. 1999, 13(3), 467-473.
[58]
Siminski, J.T.; Kavanagh, T.J.; Chi, E.; Raghu, G. Long-term maintenance of mature pulmonary parenchyma cultured in serum-free conditions. Am. J. Physiol. Cell. Mol. Physiol., 1992, 262, L105-L110.
[59]
Lekas, P.; Tin, K.L.; Lee, C.; Prokipcak, R.D. The human cytochrome P450 1A1 mRNA is rapidly degraded in HepG2 cells. Arch. Biochem. Biophys., 2000, 384, 311-318.
[60]
Lorenz, J.; Glatt, H.R.; Fleischmann, R.; Ferlinz, R.; Oesch, F. Drug metabolism in man and its relationship to that in three rodent species: monooxygenase, epoxide hydrolase, and glutathione S-transferase activities in subcellular fractions of lung and liver. Biochem. Med., 1984, 32, 43-56.
[61]
Pacifici, G.M.; Franchi, M.; Bencini, C.; Repetti, F.; Di Lascio, N.; Muraro, G.B. Tissue distribution of drug-metabolizing enzymes in humans. Xenobiotica, 1988, 18, 849-856.
[62]
Jackson, E. N.; Schneider, J.; Faux, L.R.; James, M.O. Isoform-selective glucuronidation of triclosan.FASEB J., 2013, 27, 892.811.
[63]
Uchaipichat, V.; Mackenzie, P.I.; Guo, X-H.; Gardner-Stephen, D.; Galetin, A.; Houston, J.B.; Miners, J.O. Human UDP-Glucuronlytransferases: Isoform selectivity and kinetics of 4-Methylumbellifferone and 1-Naphtol Glucuronidation, effects of organic solvents, and inhibition by Diclofenac and Probenecid. Drug Metab. Dispos., 2004, 32, 413-423.
[64]
Ripp, S.L.; Itagaki, K.; Philpot, R.M.; Elfarra, A.A. Species and sex differences in expression of flavin-containing monooxygenase form 3 in liver and kidney microsomes. Drug Metab. Dispos., 1999, 27, 46-52.
[65]
Hines, R.N. Developmental and tissue-specific expression of human flavin-containing monooxygenases 1 and 3. Expert Opin. Drug Metab. Toxicol., 2006, 2, 41-49.
[66]
Phillips, I.R.; Shephard, E.A. Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert Opin. Drug Metab. Toxicol., 2017, 13, 167-181.
[67]
Janmohamed, A.; Hernandez, D.; Phillips, I.R.; Shephard, E.A. Cell, tissue, sex and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos). Biochem. Pharmacol., 2004, 68, 73-83.
[68]
Dolphin, C.T.; Beckett, D.J.; Janmohamed, A.; Cullingford, T.E.; Smith, R.L.; Shephard, E.A.; Phillips, I.R. The flavin-containing monooxygenase 2 gene (FMO2) of humans, but not of other primates, encodes a truncated, nonfunctional protein. J. Biol. Chem., 1998, 273, 30599-30607.
[69]
Cashman, J.R.; Zhang, J. Human flavin-containing monooxygenases. Annu. Rev. Pharmacol. Toxicol., 2006, 46, 65-100.
[70]
Garattini, E.; Fratelli, M.; Terao, M. The mammalian aldehyde oxidase gene family. Hum. Genomics, 2009, 4, 119-130.

© 2024 Bentham Science Publishers | Privacy Policy