孕酮对OCTN2的抑制作用及对左旋肉碱肾脏排泄的影响

Activity Inhibition of Progesterone on OCTN2 and its Effect on L-Carnitine Renal Excretion

关键词:  肉碱/有机阳离子转运体2(OCTN2)  左旋肉碱  孕酮  肾脏排泄

Key words:  carnitine/organic cation transporter 2(OCTN2)  L-carnitine  progesterone  renal excretion

摘要:

目的 考察孕酮对肉碱/有机阳离子转运体2(carnitine/organic cation transporter 2，OCTN2)功能的影响，并探讨其是否通过抑制肾脏OCTN2功能改变左旋肉碱肾脏排泄，从而降低妊娠期血浆左旋肉碱浓度。方法 采用已构建的稳定高表达人OCTN2的MDCK-hOCTN2细胞模型，分别以米屈肼和氘代左旋肉碱为底物，考察孕酮对OCTN2的抑制作用。正常雌性ICR小鼠皮下注射孕酮，使其达妊娠晚期血清孕酮浓度，比较其与对照组小鼠左旋肉碱尿液排泄差异，以及血浆和各组织中左旋肉碱浓度差异。结果 孕酮显著抑制OCTN2对米屈肼和氘代左旋肉碱的摄取，半数抑制浓度分别为8.7 μmol·L^-1和14.0 μmol·L^-1。孕酮给药组小鼠血清孕酮浓度为462~1153 nmol·L^-1，与妊娠晚期生理浓度相当，左旋肉碱的尿液排泄量以及血浆、肝脏、肾脏和心脏中左旋肉碱浓度与对照组无显著差异。结论 孕酮显著抑制OCTN2功能，但与妊娠晚期生理浓度相当的孕酮不影响左旋肉碱的肾脏排泄及体内稳态。

Abstract:

OBJECTIVE To investigate the effect of progesterone on the activity of carnitine/organic cation transporter 2(OCTN2), and explore whether progesterone can reduce plasma L-carnitine concentration during pregnancy by inhibiting the renal OCTN2 activity and changing the renal excretion of L-carnitine. METHODS Used the established MDCK-hOCTN2 cell model with stable and high expression of human OCTN2, the inhibitory effect of progesterone on OCTN2 was investigated with mildronate and d₃-L-carnitine as substrates. Normal female ICR mice were subcutaneously injected with progesterone to make their serum progesterone concentration reach the third trimester of pregnancy, then the urinary excretion of L-carnitine and L-carnitine concentrations in plasma and tissues were determined and compared with the control group. RESULTS Progesterone reduced the accumulation of mildronate or d₃-L-carnitine in MDCK-hOCTN2 cells in a concentration-dependent manner, and the IC₅₀ values were 8.7 μmol·L^-1and 14.0 μmol·L^-1, respectively. The serum concentrations of progesterone were 462-1 153 nmol·L^-1in the treated mice, which were equivalent to the physiological concentrations in late pregnancy. Compared with the control group, there were no significant differences in the urinary excretion of L-carnitine and L-carnitine levels in plasma, liver, kidney and heart of mice in the progesterone treated group. CONCLUSION Progesterone significantly inhibites the activity of OCTN2 in vitro, however, progesterone at levels observed in late pregnancy do not affect L-carnitine renal excretion and homeostasis.