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    (1.National Demonstration Center for Experimental (Pharmacy) Education,Zunyi Medical University,Zunyi Guizhou 563099,China; 2.Department of Endocrinology,The Third Affiliated Hospital of Zunyi Medical University,Zunyi Guizhou 563000,China)

    基础医学研究

    Speciesdifferenceontestosteronemetabolisminhumansandanimals

    HeYuqi1,ZengYao1,LingLei1,LuAnjing1,DuYimei1,YangTao1,LiBoda1,PengJie2,WuQing1

    (1.National Demonstration Center for Experimental (Pharmacy) Education,Zunyi Medical University,Zunyi Guizhou 563099,China; 2.Department of Endocrinology,The Third Affiliated Hospital of Zunyi Medical University,Zunyi Guizhou 563000,China)

    ObjectiveTo investigate the species difference of testosterone metabolism among human and 7 animal species including mice,rats,guinea pigs,rabbits,dogs,pigs,sheep,and cattle.MethodsTestosterone was incubated with liver microsomes of humans and investigated animals,together with CYP-mediated metabolic reaction factors including NADP Na,glucose-6-phosphate,and glucose-6-phosphate dehydrogenase.Incubation samples were introduced into HPLC to determinate testosterone and its metabolites.Heatmap was used to visualize the metabolic profile while principle component analysis was used to tell the difference of metabolic profile among species.High resolution mass spectrometry was used to assist the identification of metabolite structures.Results6β-hydroxylation is not the unique metabolic pathway of testosterone.Eighteen NADP-dependent metabolites were observed in humans or other investigated animals.Although 6β-hydroxylation showed positive correlation with the substrate elimination,this specific metabolic pathway could not compensate all substrate consumption.Guinea pig generates the most metabolites while sheep showed the weakest capacity on testosterone metabolism.Mice,dogs,and rabbits showed the most similar metabolic profile to humans.Conclusion6β-hydroxylation metabolites of testosterone was not applicable to evaluate the CYP 3A activity of all species.Mice,dogs,and rabbits are recommended in pre-clinical trial if the target is proved to be metabolized by human CYP 3A4. ......