The Expression And The Capability Of Stress To Adriamycin Of MDR₁ Gene In Cochlea Lateral Wall Of Guinea Pig

Objective To study the expression of MDR1 gene and the influence of adriamycin on it in cochlea lateral wall of guinea pig, to make sure the capability of stress to adriamycin, and hence to provide the theoretical basis for the mechanism of susceptivity to some ototoxicity drugs in infant. Methods White guinea pigs with red eyes were choosed randomly from 1-2 weeks,3 weeks and 4 weeks guinea pigs,respectively divided into three groups:control group,N.S group and adriamycin group. Guinea pigs were administered an intravenous injection of 30mg/kg adriamycin or N.S. 24 hours later, the animals were sacrificed ,and the cochlea lateral wall were then immediately removed after the endolymph was drawn by the siphon from the basal turn of cochlea. The expression and the quantity changes of the MDR1 mRNA in the cochlea lateral wall of guinea pigs were observed by in situ hybridization and RT-PCR. Furthermore, the ADM concentration in endolymph were measured by high performance liquid chromatography.Results (1) The results of in situ hybridization showed that the MDR1mRNA asymmetrically distributed in cells from cochlea lateral wall of guinea pigs.(2) The expression of MDR1 gene enhanced during aging.The density ratio of MDR1mRNA to β-actin was significantly different among three age groups(P<0.05).In addition, the density ratio of MDR1mRNA to β-actin of 4-week-group is largest,and that of 3-week-group is smallest.(3) Regardless of group, the density ratio of MDR1mRNA to β-actin of the adriamycin group was significantly different from the control group (P<0.05). In contrast , there was no significant difference between the N.S group and the control group (P>0.05).(4) After 24 hours administered injection of 30mg/Kg adriamycin,the gain of MDR1mRNA in 1-2 weeks group was obviously lower than that of 3-week-group and 4-week-group(P<0.05),yet there appeared no significant difference between 3-week-group and 4-week-group(P>0.05). (5) According to HPLC,it was shown that extrusion of adriamycin by cochlea lateral wall was age-dependent.The concentration of adriamycin in endolymph of 3-week-group was approximately similar to 4-week-group (P>0.05). Compared with 3-week-group or 4-week-group,that of 1-2 weeks group wassignificantly higher(P<0.05). Conclusions (1) The expression of MDR1mRNA in cochlea lateral wall alter along with the growth of guinea pig, extrusive transport of which mediates may come to be mature with aging. (2) MDR1 gene may be a stress gene which can be induced by adriamycin.The stress capability of MDR1 gene in normal cochlea lateral wall of guinea pig may be increasing with it's growing,and level off when reached some stage.(3) MDR1 gene and P-gp may take part in the extrusive transport.The physiological function as an efflux pump can decrease the accumulation of some ototoxicity drugs in inner ear,and avoid the inner ear damage.In conclusion,the present study demonstrated that the expression and the capability of stress to some ototoxicity substance of MDR1 gene in the cells from cochlea lateral wall of guinea pig is age-dependent,It appeared to contribute to a new theoretical basis for the mechanism of susceptivity to some ototoxicity drugs in infant.