Metabolism of non-steroidal anti-inflammatory drugs (NSAIDs) by Streptomyces griseolus CYP105A1 and its variants |
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| Institution: | 1. Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan;2. Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan;3. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, KitashirakawaOiwake-cho, Sakyo-ku, Kyoto, 606–8502, Japan;4. RIKEN Spring-8 Center, Harima Institute, Sayo, Hyogo, 679-5148, Japan;1. Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil;2. Analytical Services International (ASI) Ltd., St George''s – University of London, Cranmer Terrace, London, SW17 0RE, UK;3. Campinas Poison Control Center, Faculty of Medical Sciences, State University of Campinas (UNICAMP), Campinas, SP, Brazil;4. Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;5. NPPNS, Departamento de Ciências Biomoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo - USP, Ribeirão Preto, São Paulo, Brazil;6. Institute of Chemistry, University of Tartu, 14a Ravila Street, 50411, Tartu, Estonia;7. Pharmaceutical Sciences Clinical Academic Group, King''s College London, London, United Kingdom;8. Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom;9. Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil;1. Discovery Technology Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan;2. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan;1. Central Institute for Experimental Animals, Kawasaki, Japan;2. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;1. The Department of Clinical Pharmacology, Faculty of Medicine Jazan University, Saudi Arabia;2. American University of Health Sciences, Signal Hill, CA, USA;3. Ophthalmology, University of California, San Francisco, CA, USA;4. Ophthalmology, NYU Medical Center, NY, USA;1. Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan;2. Laboratory of Pharmaceutics, Department of Biomedical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan;3. Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, Japan;4. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;5. Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan;1. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China;2. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China;3. The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230032, PR China;4. Center for Scientific Research of Anhui Medical University, Hefei, 230032, PR China;5. Hefei Kaifan Analytical Technology Co., Ltd., Hefei, 230051, PR China |
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| Abstract: | In the field of drug development, technology for producing human metabolites at a low cost is required. In this study, we explored the possibility of using prokaryotic water-soluble cytochrome P450 (CYP) to produce human metabolites. Streptomyces griseolus CYP105A1 metabolizes various non-steroidal anti-inflammatory drugs (NSAIDs), including diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, meclofenamic acid, and ibuprofen. CYP105A1 showed 4′-hydroxylation activity towards diclofenac, mefenamic acid, flufenamic acid, tolfenamic acid, and meclofenamic acid. It should be noted that this reaction specificity was similar to that of human CYP2C9. In the case of mefenamic acid, another metabolite, 3′-hydroxymethyl mefenamic acid, was detected as a major metabolite. Substitution of Arg at position 73 with Ala in CYP105A1 dramatically reduced the hydroxylation activity toward diclofenac, flufenamic acid, and ibuprofen, indicating that Arg73 is essential for the hydroxylation of these substrates. In contrast, substitution of Arg84 with Ala remarkably increased the hydroxylation activity towards diclofenac, mefenamic acid, and flufenamic acid. Recombinant Rhodococcus erythrocyte cells expressing the CYP105A1 variant R84A/M239A showed complete conversion of diclofenac into 4′-hydroxydiclofenac. These results suggest the usefulness of recombinant R. erythropolis cells expressing actinomycete CYP, such as CYP105A1, for the production of human drug metabolites. |
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| Keywords: | Non-steroidal anti-inflammatory drugs NSAIDs Cytochrome P450 CYP105 Drug metabolism NSAIDs"} {"#name":"keyword" "$":{"id":"kwrd0040"} "$$":[{"#name":"text" "_":"non-steroidal anti-inflammatory drugs P450 or CYP"} {"#name":"keyword" "$":{"id":"kwrd0050"} "$$":[{"#name":"text" "_":"cytochrome P450 UPLC"} {"#name":"keyword" "$":{"id":"kwrd0060"} "$$":[{"#name":"text" "_":"Ultra Performance Liquid Chromatography HPLC"} {"#name":"keyword" "$":{"id":"kwrd0070"} "$$":[{"#name":"text" "_":"High Performance Liquid Chromatography |
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