Yoshimura T, Schwab A J, Tao L, Barker F, Pang K S
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Am J Physiol. 1998 Jan;274(1):G10-20. doi: 10.1152/ajpgi.1998.274.1.G10.
The hepatic transport of hippuric acid (HA), a glycine-conjugated metabolite of benzoic acid that exhibits only modest plasma albumin binding (binding association constant of 2.1 x 10(3) M-1), was studied in the single-pass perfused rat liver (12 ml/min), using the multiple indicator dilution (MID) technique. The venous recovery of [3H]HA on portal venous injection of a MID dose containing a mixture of a set of noneliminated reference indicators and [3H]HA revealed a survival fraction of unity, corroborating the lack of disappearance of bulk HA from plasma. When the outflow recovery was fitted to the barrier-limited model of Goresky et al. (C.A. Goresky, G. G. Bach, and B. E. Nadeau. J. Clin. Invest. 52: 991-1009, 1973), the derived influx (P(in)S) and efflux (P(out)S) permeability-surface area products were found to be dependent on the concentration of HA (1-930 microM); P(in)S and P(out)S were approximately 3.5 times the plasma flow rate at low HA concentration, but decreased with increasing HA concentration. All values, however, greatly exceeded the expected contribution from passive diffusion, because the equilibrium distribution ratio of chloroform to buffer for HA was extremely low (0.0001 at pH 7.4). The tissue equilibrium partition coefficient (P(in)/P(out), or ratio of influx to efflux rate constants, k1/k-1) was less than unity and decreased with concentration. The optimized apparent Michaelis-Menten constant and maximal velocity were 182 +/- 60 microM and 12 +/- 4 nmol.s-1.g-1, respectively, for influx and 390 +/- 190 microM and 29 +/- 13 nmol.s-1.g-1, respectively, for efflux. In the presence of L-lactate (20 mM), however, P(in)S for the uptake of HA (174 +/- 3 microM) was reduced. Benzoic acid (10-873 microM) was also effective in reducing hepatic uptake of HA (5.3 +/- 0.9 microM). These interactions suggest that MCT2, the monocarboxylate transporter that mediates the hepatic uptake of lactate and other monocarboxylic acids, may be involved in HA transport.
马尿酸（HA）是苯甲酸的甘氨酸共轭代谢产物，其血浆白蛋白结合率仅为中等水平（结合缔合常数为2.1×10³ M⁻¹），本研究采用多指示剂稀释（MID）技术，在单通道灌注大鼠肝脏（12 ml/min）中研究了其肝脏转运情况。门静脉注射含有一组未消除的参考指示剂和[³H]HA混合物的MID剂量后，门静脉中[³H]HA的静脉回收率显示存活分数为1，证实了血浆中大量HA没有消失。当将流出回收率拟合到Goresky等人（C.A. Goresky、G.G. Bach和B.E. Nadeau。《临床研究杂志》52: 991 - 1009, 1973）的屏障限制模型时，发现推导的流入（P(in)S）和流出（P(out)S）通透率 - 表面积乘积取决于HA的浓度（1 - 930 μM）；在低HA浓度下，P(in)S和P(out)S约为血浆流速的3.5倍，但随HA浓度增加而降低。然而，所有值都大大超过了被动扩散的预期贡献，因为HA在氯仿与缓冲液之间的平衡分配比极低（在pH 7.4时为0.0001）。组织平衡分配系数（P(in)/P(out)，即流入与流出速率常数之比，k1/k - 1）小于1且随浓度降低。流入的优化表观米氏常数和最大速度分别为182±60 μM和12±4 nmol·s⁻¹·g⁻¹，流出的分别为390±190 μM和29±13 nmol·s⁻¹·g⁻¹。然而，在L - 乳酸（20 mM）存在的情况下，HA摄取的P(in)S（174±3 μM）降低。苯甲酸（10 - 873 μM）也能有效降低肝脏对HA的摄取（5.3±0.9 μM）。这些相互作用表明，介导肝脏摄取乳酸和其他一元羧酸的单羧酸转运蛋白MCT2可能参与HA的转运。
