Species Difference between Cynomolgus Monkeys and Humans on Cytochromes P450 2D and 3A-Dependent Drug Oxidation Activities in Liver Microsomes
スポンサーリンク
概要
- 論文の詳細を見る
Cynomolgus monkeys [Macaca fascicularis (mf)] are widely used to determine pharmacokinetics and toxicological potential of many drug candidates as human models in the drug discovery and development. Cytochrome P450s (P450, CYP), one of the most important enzymes in drug metabolism, in monkey livers are generally similar to corresponding human P450s exhibiting high degrees of homologies in cDNAs and amino acid sequences. Species differences regarding important liver P450 3A and 2D function were examined between cynomolgus monkeys and humans using typical human P450 probe reactions using midazolam (a P450 3A marker), dextromethorphan and bufuralol (P450 2D markers). P450 3A-mediated midazolam 1-hydroxylation activities in liver microsomes from individual monkey were highly correlated with midazolam 4-hydroxylation activities but not correlated with dextromethorphan N-demethylation activities. Recombinant monkey CYP2D17 and CYP2D44 catalyzed dextromethorphan O- and N-demethylations as well as monkey mfCYP3A4 and mfCYP3A5 did. On the other hand, contributions of corresponding P450 2D6 and P450 3A4/5 to dextromethorphan N- and O-demethylations, in human liver microsomes were negligible under the present conditions. From these results, monkey P450 2D and 3A enzymes might have broader substrate specificity toward dextromethorphan oxidation than those in human livers. Special attention should be paid when enzymatic and pharmacokinetic data are extrapolated from monkeys to humans.
著者
-
Yamazaki Hiroshi
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
-
Murayama Norie
Laboratory Of Drug Metabolism And Pharmacokinetics Showa Pharmaceutical University
-
Emoto Chie
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
-
Iwasaki Kazuhide
Department Of Pharmacokinetics Dynamics And Metabolism Nagoya Laboratories Pfizer Inc.
-
Uno Yasuhiro
Shin Nippon Biomedical Laboratories
-
IWASAKI Kazuhide
Shin Nippon Biomedical Laboratories
-
Yamazaki Hiroshi
Laboratory Of Drug Metabolism And Pharmacokinetics Showa Pharmaceutical University
-
Koizumi Ryo
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University
-
Utoh Masahiro
Shin Nippon Biomedical Laboratories
関連論文
- Genotoxic Activation of the Environmental Pollutant 3-Nitrobenzanthrone by Human Cytochrome P450 Enzymes Expressed in Salmonella typhimurium umu Tester Strains
- Human blood concentrations of dichlorodiphenyltrichloroethane (DDT) extrapolated from metabolism in rats and humans and physiologically based pharmacokinetic modeling
- 肝P450等の薬物代謝酵素活性を指標とした日本発新規ヒト型モデル動物"マイクロミニブタ"の非臨床試験における高い将来性
- 日本人肝におけるフラビン含有モノオキシゲナーゼ3発現の個人差 : 肝転写因子との相関
- Complex Mechanism Underlying Transcriptional Control of the Haplotyped Flavin-containing Monooxygenase 3 (FMO3) Gene in Japanese : Different Regulation between Mutations in 5'-Upstream Distal Region and Common Element in Proximal Region
- 高気圧酸素療法を施した患者の抗がん薬カルボプラチン血漿中濃度測定用HPLC法について
- Drug metabolism and toxicity in chimeric mice with humanized liver
- Missense and Nonsense Mutations of the Flavin-containing Monooxygenase 3 Gene in a Japanese Cohort
- Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population.
- 日本人トリメチルアミン尿症の原因となるフラビン含有モノオキシゲナーゼ3遺伝子の新規遺伝子変異
- Two Novel Single Nucleotide Polymorphisms (SNPs) of the FMO3 Gene in Japanese
- Human Blood Concentrations of Dichlorodiphenyltrichloroethane (DDT) Extrapolated from Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling
- Microminipig, a Non-rodent Experimental Animal Optimized for Life Science Research:In Vivo Proarrhythmia Models of Drug-Induced Long QT Syndrome: Development of Chronic Atrioventricular Block Model of Microminipig
- Drug Metabolism and Toxicity in Chimeric Mice with Humanized Liver
- Pharmacokinetic Investigation of Increased Efficacy Against Malignant Gliomas of Carboplatin Combined With Hyperbaric Oxygenation
- Twenty One Novel Single Nucleotide Polymorphisms (SNPs) of the CYP2A6 Gene in Japanese and Caucasians
- Activities of Cytochrome P450 Enzymes in Liver and Kidney Microsomes from Systemic Carnitine Deficiency Mice with a Gene Mutation of Carnitine / Organic Cation Transporter
- CYP3A5 Contributes Significantly to CYP3A-mediated Drug Oxidations in Liver Microsomes from Japanese Subjects
- In vivo Evaluation of Coumarin and Nicotine as Probe Drugs to Predict the Metabolic Capacity of CYP2A6 Due to Genetic Polymorphism in Thais
- Novel Nonsynonymous Polymorphisms of the CYP1A1 Gene in Japanese
- Toxicological roles of human and rodent CYP2As in the mutagenic activation of N-nitrosamines.(GENERAL SESSION BY ORAL PRESENTATION)(DRUG METABOLISM)
- Novel Mutations of the CYP2A6 Gene in a Thai Population with Lowered Capacity of Coumarin 7-Hydroxylation
- Two Novel Haplotypes of CYP2D6 Gene in a Japanese Population
- Eighteen Novel Polymorphisms of the CYP2A13 Gene in Japanesse
- Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling
- Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition
- AN ENZYMIC MECHANISM FOR MUTAGENIC ACTIVATION OF CARCINOGENIC AMINOAZO DYES
- Species Difference between Cynomolgus Monkeys and Humans on Cytochromes P450 2D and 3A-Dependent Drug Oxidation Activities in Liver Microsomes
- Bonitos with Low Content of Malodorous Trimethylamine as Palliative Care for Self-reported Japanese Trimethylaminuria Subjects
- Evaluation of drug toxicity with hepatocytes cultured in a micro-space cell culture system(CELL AND TISSUE ENGINEERING)
- CYP1B1 is polymorphic in cynomolgus and rhesus macaques
- Cynomolgus Macaque CYP4 Isoforms Are Functional, Metabolizing Arachidonic Acid
- Dose-dependent Effects of Cigarette Smoke on Blood Biomarkers in Healthy Japanese Volunteers : Observations from Smoking and Non-smoking
- Comparison of Cytochrome P450 3A Enzymes in Cynomolgus Monkeys and Humans
- Regional Distribution of Cytochrome P450 mRNA Expression in the Liver and Small Intestine of Cynomolgus Monkeys
- Identification and Characterization of CYP2C18 in Cynomolgus Macaque (Macaca fascicularis)
- Identification and Characterization of CYP2B6 cDNA in Cynomolgus Macaques (Macaca fascicularis)
- CYP2D6 PM/EM肝細胞を用いたデキストロメトルファン(DEX)代謝の評価
- A Major Genotype in UDP-glucuronosyltransferase 2B15
- Microminipig, a Non-rodent Experimental Animal Optimized for Life Science Research : In Vivo Proarrhythmia Models of Drug-Induced Long QT Syndrome : Development of Chronic Atrioventricular Block Model of Microminipig
- Evaluation of cytotoxic potential of cored soft contact lenses with adsorbed active ingredients from over-the-counter eye drops
- Lung tumorigenesis promoted by anti-apoptotic effects of cotinine, a nicotine metabolite through activation of PI3K/Akt pathway
- Molecular Cloning, Functional Expression, and Characterization of Isolectin Genes of Hemolytic Lectin CEL-III from the Marine Invertebrate Cucumaria echinata
- Simultaneous pharmacokinetics assessment of caffeine, warfarin, omeprazole, metoprolol, and midazolam intravenously or orally administered to Microminipigs