Reoxygenation after cold hypoxic storage of cultured precision-cut rat liver slices: effects on cellular metabolism and drug biotransformation |
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| Affiliation: | 3. Radiology Unit, G. Rummo Hospital, Benevento, Italy;4. Infectious Diseases Unit, G. Rummo Hospital, Benevento, Italy;1. I. Medizinische Klinik und Poliklinik, Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131 Mainz, Germany;2. Department of Pathology, Klinikum Bayreuth, Bayreuth, Germany;3. Optiscan Pty Ltd., Notting Hill, Vic., Australia;1. Departamento de Ciencias Químicas y Farmacéuticas, Universidad Arturo Prat, Iquique, Chile, Avenida Arturo Prat 2120, Casilla 121 Iquique, Chile;2. Departamento Química Orgánica, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Casilla 306 Santiago, Chile;3. Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie (PMNT 7369), Département des Sciences Pharmaceutiques, Université Catholique de Louvain, 73, avenue E. Mounier, 1200 Bruxelles, Belgium;1. Division of Genetic Diagnosis, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;2. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108-8639, Japan;3. Department of Biomedical Resources, National Institute of Biomedical Innovation, Ibaraki, Osaka, Japan;4. Division of Molecular Life Science, School of Medicine, Tokai University, Shimokasuya 134, Isehara, Kanagawa 259-1193, Japan;1. Instituto de Investigaciones Biomédicas de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain;2. Pharmacy Faculty, Monastir, Tunisia;3. Serveis Cientifico-Técnics,, UB-IDIBAPS, Barcelona, Spain;4. Animal Biology Department of Animal Biology, University of Pavia, Pavia, Italia;5. CHU-Edouard Herriot, Lyon, France;6. IDIBAPS, Barcelona, Spain |
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| Abstract: | Cultured rat precision-cut liver slices (PCLS) were used to study the influence of hypothermic preservation and reoxygenation at 37°C on cellular metabolism and drug biotransformation. Cold hypoxic storage caused a depressed metabolism in rat liver slices, but reoxygenation for 8 h at 37°C partially restored the levels of both ATP and GSH and totally restored the capacity to synthesize proteins. Metabolism of midazolam (CYP3A-dependent oxidation) by cold preserved liver slices was decreased by 30% but no further affected by reoxygenation, showing the same profile as freshly cut slices. Such a reoxygenation at 37°C is accompanied by a dramatic loss of CYP3A2 protein while CYP3A1 protein was unaffected. These results suggest that CYP3A2 did not play a major role in midazolam oxidation. Such results are not consistent with a putative reoxygenation injury but rather with cold hypoxic damage. Since cold preserved liver slices did not respond to bacterial endotoxin stimulation (lipopolysaccharides), a minor role of non-parenchymal cells is suggested as mediators for deleterious effects developed during the cold storage. |
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