金匮肾气丸对伊马替尼所致小鼠生殖毒性及其在血、睾中含量影响研究

Effect of Jinkui Shenqi Pill on Reproductive Toxicity of Imatinib-induced Mice and Its Content in Blood and Bletilla Striata

目的:观察金匮肾气丸(JIN)对伊马替尼(imatinib)所致雄性小鼠生殖毒性的拮抗作用,采用液质联用技术测定其对伊马替尼在小鼠血液及睾丸中含量影响,研究其存效减毒可能作用机制。方法:将70只健康雄性昆明小鼠随机分为对照组(Cont),伊马替尼低、中、高剂量染毒组,金匮肾气丸低、中、高剂量拮抗组;染毒组和拮抗组小鼠分别给予66.70、100.00、133.33mg/(kg·d)的伊马替尼溶液,1次/d,每周6 d,连续8周;拮抗组小鼠给予伊马替尼的同时,分别给予660.00、1330.00、2670.00 mg/(kg·d)金匮肾气丸水溶液,1次/d,每周6 d,8周后颈脱位法处死小鼠,计算小鼠睾丸脏器系数及精子数量,采用液质联用技术测定小鼠血液及睾丸组织中伊马替尼浓度。结果:H-IM组睾丸系数下降趋势明显,提示伊马替尼高剂量组毒性较强,使睾丸相对重量下降,而经金匮肾气丸治疗后,睾丸系数均有上升趋势,差异无统计学意义(P>0.05);与Cont组比较,染毒低、中、高组小鼠精子数量均有减少,同剂量金匮肾气丸与伊马替尼联合用药组与伊马替尼组相比,均能显著性增加精子数量,差异有统计学意义(P<0.01);各给药组中M-IM组小鼠血液中伊马替尼含量最高,联合金匮肾气丸用药后,各组小鼠血液中伊马替尼浓度均有所增加,仅见M-IM组与M-IM+JIN组血液中伊马替尼含量有显著性差异(P<0.05);各给药组精液中均能检测到伊马替尼,其中M-IM组与M-IM+JIN组药物含量有统计学差异(P<0.01),且联合用药后,中剂量组小鼠精液中伊马替尼浓度有所降低。结论:伊马替尼染毒对小鼠有生殖毒性作用,金匮肾气丸可通过降低小鼠睾丸中伊马替尼含量,拮抗其所致生殖毒性,其作用机制有待进一步研究。

Objective To observe the antagonistic effect of Jinkui Shenqi Pill on reproductive toxicity of imatinib induced male mice,the effect of imatinib in blood and testis content in mice was determined by liquid-mass spectrometry.Methods 70 healthy male Kunming mice were divided randomly into low、medium and high dose imatinib groups;low、medium and high antagonistic groups of Jinkui Shenqi Pill and control group.Imatinib groups of mice were given imatinib solution by gavage with the concentration of 66.70、100.00、133.33 mg/(kg·d)once a day for 6 days a week continuously;The antagonistic groups mice were given with Jinkui Shenqi Pill solution by gavage with the concentration of 660.00、1330.00、2670.00 mg/(kg·d)once a day for 6 days a week continuously.After medication with 8 weeks,mice were put to death and calculating mice testicular viscera and counting the number of sperm,determination of imatinib in mouse blood and left testicular tissue by liquid-mass spectrometry.Results Testicular viscera decreased in H-IM group indicated that toxicity of imatinib was stronger in high dose group,drop the relative weight of the testicles,after treatment of Jinkui Shenqi Pill,the testicular viscera all increased,there were no significant differences(P>0.05);Compared with the control group,the sperm count of mice with low,medium and high toxicity was decreased;Compared with imatinib group in the same dose of Jinkui Shenqi pills and imatinib combination,all significantly increased sperm count,there were significant differences(P<0.01);Imatinib levels were highest in the blood of M-IM groups in each group,there was only significant difference in imatinib in blood between M-IM and M-IM JIN groups(P<0.05);Imatinib was detected in semen of each administration group,M-IM group and M-IM JIN group were significant differences(P<0.01).The concentration of imatinib in semen of mice in medium dose group was decreased after administration by Jingkui Shenqi pills.Conclusion Imatinib has reproductive toxicity in mice,and Jinkui Shenqi Pill can antagonize the reproductive toxicity induced by imatinib.