2007 Fiscal Year Final Research Report Summary
Comparative Biochemistry of Primate Drug-Metabolizing Enzymes for the Toxicological Evaluation of Chemical Compounds
| Project/Area Number |
17390035
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Environmental pharmacy
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| Research Institution | Okayama University |
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Principal Investigator |
NARIMATSU Shizuo Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Dentistry Professor (20113037)
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| Co-Investigator(Kenkyū-buntansha) |
HANIOKA Nobumitsu Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Dentistry Associate Professor (70228518)
MASUDA Kazufumi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Dentistry Assistant Professor (00243486)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Crab-eating monkey / Marmoset / Japanese monkey / Drug-metaholizing enzyme / cDNA cloning / Hetelorogus Expression System / Crvoseserved hepatocytes / mRNA level |
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| Research Abstract |
To establish the system for the evaluation of toxicity of chemical compounds including medicines and environmental pollutants, we conducted this project in which drug-metabolizing functions of monkeys such as Japanese monkeys, crab-eating monkeys and marmosets are compared with those of humans, resulting in more accurate extrapolation of the data obtained from monkeys into humans. Using primers designed on the basis of human genes encoding corresponding enzymes, RT-PCR was performed, and cDNAs encoding monkey CYP (CYP1A2 from Japanese monkey, CYP2E1 from Japanese monkey and marmoset) and UGT enzymes (UGT1A6 and UGT2B20) were cloned in Escherichia coli. Each of these cDNAs was inserted into an appropriate plasmid vector with which yeast cells or insect cells were transfected to express corresponding proteins. The functions of the recombinant enzymes were compared with those of human othologous enzymes. As results, the properties of CYP1A2 and CYP2E1 were similar between monkeys and humans, whereas those of CYP2C8 and UGT enzymes were considerably different. In addition, we examined the effects of typical inducers (dexamethasone, omeprazole and rifampicin) of drug-metabolizing enzymes on the mRNA levels of various drug-metabolizing enzymes in primary culture system of cryoreserved hepatocytes from crab-eating monkeys and humans. Following the treatment of the hepatocytes with the inducers, some differences were observed between monkeys and humans in the profile of the alteration in mRNA levels for various drug-metabolizing enzymes. Together with the results obtained, further research on this line will establish an appropriate system by which we can accurately predict the toxicity in humans of promising candidates for medicines or chemical compounds for industrial products from the data obtained in monkeys.
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Research Products
(58 results)
