Effects Of Exposure To High Altitude Hypoxia On The MDR1, MRP1 And BCRP

Objective:To investigate the drug transporters MDR1,MRP1 and BCRP in rats in special environment of high altitude hypoxia,and to provide the guidance to explain drug's metabolism in special environment of high altitude hypoxia,and give valuable references to clinical reasonable medication in plateau areas.Methods:SD rats were randomly divided into seven groups,and every group had five male and five female rats.The plain group?P?included 10 healthy rats living at an altitude of 400 m in the city of Xi'an in northwest China's Shanxi Province.The acute middle altitude hypoxia group?AMH?and the chronic middle altitude hypoxia group?CMH?comprised healthy rats living at plain level,but they received a 24-hour acute exposure and a 40-day chronic exposure to middle altitude prior to drug administration.The rats in these two groups were transported by bus to Gonghe County,which is in northwestern China's Qinghai Province,to an altitude of 2 900 m.The acute high altitude hypoxia group?AHH?and the chronic high altitude hypoxia group?CHH?comprised healthy rats living at plain level,but they received a 24-h acute exposure and a 40-day chronic exposure to high altitudes prior to drug administration.The rats in these two groups were transported by bus to Huashixia Town,which is in northwestern China's Qinghai Province,to an altitude of 4 200 m.The CMH-R group comprised healthy rats living at plain level.After received a40-day chronic exposure to moderate altitude of 2 900 m,the rats were transported by bus to Xining City,which is in northwestern China's Qinghai Province,to an altitude of 2 200 m.The CHH-R group comprised healthy rats living at plain level.After received a 40-day chronic exposure to high altitude of 4 200 m,the rats were transported by bus to Xining City.The changes of physiological indexes of rats,such as Sc O₂,HGB,RBC,WBC,BIL and ALB,were measured under high altitude hypoxia.Enzyme linked immunosorbent assay?ELISA?was used to determinate the protein expression of MDR1,MRP1 and BCRP in rats,and the mRNA expression of MDR1,MRP1 and BCRP was determinated by RT-PCR method.Low pressure chamber simulating high altitude hypoxia environment was used to evaluate the specific substrates of MDR1 and BCRP,MRP1.Plain SD rats living at Xi'an city of Shanxi province were randomly divided into four groups,including control group?Xi'an,400 m,PaO2 20 kPa?,positive control group?Xi'an,400 m altitude,PaO2 20kPa?,acute hypoxia group?Xining city,low pressure chamber for 4 days,5 000 m,PaO₂ 10.4 kPa?and chronic hypoxia group?Xining city,low pressure chamber for 28days,5 000 m,PaO₂ 10.4 kPa?.To evaluate the effect of high altitude hypoxia on the absorption of specific substrates of MDR1,MRP1 and BCRP was measured in rats intestine by in intestinal perfusion method.Results:Compared with the P group,The ScO2 of rats from the AMH,CMH,AHH,CHH,CMH-XN and CHH-XN groups was significantly decreased by 11.0%,8.8%,14.9%,12.4%,7.4%and 7.3%,respectively,and the value of HGB was significantly increased by 10.8%,16.9%,15.5%,32.6%,15.8%and 20.5%,respectively.The RBC of rats from the AMH,CMH,AHH,CHH,CMH-XN and CHH-XN groups was significantly increased by 22.5%,27.6%,29.2%,33.6%,22.2%and 25.6%,respectively,and the BIL of rats from the CMH,AHH,CHH,CMH-XN and CHH-XN groups was significantly increased by 5.2%,4.7%,12.4%,6.4%and9.9%,respectively.The ALB and WBC have no significant differences in 6 groups compared with the P group.Compared with the P group,the protein expression of MDR1 was significantly decreased by 16.3%,27.3%,27.3%,33.1%,39.0%and 41.3%in the AMH,CMH,AHH,CHH,CMH-XN and CHH-XN,respectively,and the mRNA expression of MDR1 was significantly decreased by 33.0%,34.0%,48.1%,47.2%,48.1%and 52.8%,respectively.Compared with the P group,the protein expression of MRP1 was significantly decreased by 19.4%,31.7%,34.0%,50.9%,52.0%and 56.0%in the AMH,CMH,AHH,CHH,CMH-XN and CHH-XN,respectively,and the mRNA expression of MRP1 was significantly decreased by18.9%,23.4%,36.9%,30.6%,27.0%,and 29.7%,respectively.Compared with the P group,the protein expression of BCRP was significantly decreased by 25.9%,38.6%,37.0%,54.1%,53.1%,and 66.8%in the AMH,CMH,AHH,CHH,CMH-XN and CHH-XN,respectively,and the mRNA expression of BCRP was significantly decreasedby14.8%,34.8%,44.3%,40.9%,51.3%,and43.5%,respectively.Compared with the control group,the effective intestinal permeability(P_eff)of MDR1 substrates was increased by 95.5%and 168.7%in acute hypoxia group and chronic hypoxia group,respectively,and Peff of MPR1 substrates in acute hypoxia group and chronic hypoxia group was increased by 160.0%and 235.5%,respectively.The P_eff of BCRP substrates in acute hypoxia group and chronic hypoxia group was increased by 59.3%and 128.1%compared with the control group,respectively.In addition,the absorption rate constant increased significantly under hypoxia.It may be that in low oxygen conditions,the three transporters reduce the out of their specific substrate.Conclusion:The protein and mRNA expression of MDR1,MRP1 and BCRP were significantly decreased in special environment of high altitude hypoxia.The absorption rate constant and the effective intestinal permeability of the specific substrate increased significantly,which may lead to the reduction of the substrate of MDR1,MRP1 and BCRP,and the increase of intestinal absorption.