Contraluminal p-aminohippurate transport in the proximal tubule of the rat kidney

Abstract

Using the stop-flow peritubular capillary microperfusion method contraluminal transport of corticosteroids was investigated (a) by determining the inhibitory potency (apparent Ki values) of these compounds against p-aminohippurate (PAH), dicarboxylate (succinate) and sulphate transport and (b) by measuring the transport rate of radiolabelled corticosteroids and its inhibition by probenecid. Progesterone did not inhibit contraluminal PAH influx but its 17 alpha- and 6 beta-hydroxy derivatives inhibited with an app. Ki of 0.36 mmol/l. Introduction of an OH group in position 21 of progesterone, to yield 11-deoxycorticosterone, augments the inhibitory potency considerably (app. Ki, PAH of 0.07 mmol/l). Acetylation of the OH-group in position 21 of 11-deoxycorticosterone, introduction of an additional hydroxy group in position 17 alpha to yield 11-deoxycortisol or in position 11 to yield corticosterone brings the app. Ki, PAH back again into the range of 0.2-0.4 mmol/l. Acetylation of corticosterone or introduction of a third OH group to yield cortisol does not change the inhibitory potency, but, omission of the 21-OH group or addition of an OH group in the 6 beta position reduces or abolishes it. Cortisol and its derivatives prednisolone, dexamethasone and cortisone exert similar inhibitory potencies (app. Ki, PAH 0.12-0.27 mmol/l). But again, omission of the 21-OH group in cortisone or addition of a 6 beta-OH group reduces or even abolishes the inhibitory potency against PAH transport. The interaction of corticosterone was not changed when 11 beta, 18-epoxy ring (aldosterone) was formed. On the other hand, the interaction was considerably augmented if the 11-hydroxy group was changed to an oxo group in 11-dehydrocorticosterone (app. Ki, PAH 0.02 mmol/l). When the A ring of corticosterone is saturated and reduced to 3 alpha, 11 beta-tetrahydrocorticosterone the inhibitory potency is not changed very much. But if more than four OH or oxo groups are on the pregnane skeleton or if the OH in position 21 is missing, the inhibitory potency decreases drastically (app. Ki, PAH 0.7-1.7 mmol/l). Introduction of a 21-ester sulphate into corticosterone, cortisol and cortisone does not change app. Ki, PAH very much. Glucuronidation, however, reduces it (app. Ki, PAH approximately 1.2 mmol/l). None of the tested corticosteroids interacts, in concentrations applicable, with dicarboxylate transport and only the sulphate esters interact with sulphate transport. Radiolabelled cortisol, D-aldosterone, 11-dehydrocorticosterone, and corticosterone are rapidly transported into proximal tubular cells. With the latter three compounds no sign of saturation and no transport inhibition with probenecid could be seen.(ABSTRACT TRUNCATED AT 400 WORDS)

Luminal transport step of para -aminohippurate (PAH): transport from PAH-loaded proximal tubular cells into the tubular lumen of the rat kidney in vivo

“…c : Fig. 10 The 2-s influx of PAH from PAH-loaded proximal tubular cells into the tubular lumen in vivo: missing effect of different substances which interact with the contraluminal PAH transport system [35,37]. Each compound was added at a concentration of 5 mmol/l to the luminal perfusate.…”

Demonstration of a Probenecid-Inhibitable Anion Exchanger Involved in the Release of Cortisol and cAMP and in the Uptake of <i>p</i>-Aminohippurate in Bovine Adrenocortical Cells

“…In the proximal tubule of the rat kidney, probenecid-inhibitable transport of cortisol via the p-aminohippurate (PAH) transport system has been described [6]. Recently we demonstrated that adrenocorticotropic hormone (ACTH) stimulated cortisol release from bovine adrenocortical cells was inhibited by probenecid and trans-stimulated by PAH [7].…”

“…In the liver, transport of cortisol by an organic anion transporter, oatp [23], has been described [24], whereas in Steffgen/Rohrbach/Beery/Ersoy/Jarry/ Metten/Bornstein/Müller/Burckhardt the kidney probenecid-inhibitable transport of cortisol via the basolateral PAH/anion exchanger, OAT1 or ROAT [18,25,26], has been reported [6]. Recently, we demonstrated [7] that ACTH-stimulated cortisol release from bovine adrenocortical cells was reduced by probenecid, an inhibitor of both of these transport systems [13,27].…”

Renal transport mechanisms for xenobiotics: chemicals and drugs

“…However, OH, NH-CO-CH3, and O-C2H 5 groups also interact with the carrier presumably by hydrogen bond formation. In the same direction points the fact that many corticosteroid hormones interact with the contraluminal PAH transporter [26], whereby the spatial orientation of OH groups is important. Thus, hydrophobicity, negative charge strength (electron-attracting power), and hydrogen bond formation in favorable spatial orientation determine interaction with the PAH transporter.…”

“…As depicted in Fig. 1, the characteristics of the luminal transport system for monocarboxylates (lactate) [14,15], contraluminal and luminal transport systems for dicarboxylates (succinate) [12,16], sulfate [4,[17][18][19], and hydrophobic organic cations [tetraethylammonium (TEA) or Nl-methyl-nicotinamide (NMeN)] [5,25,27], as well as the contraluminal transport system for hydrophobic organic anions (para-aminohippurate, PAH) [20][21][22][23]26] were well defined. The luminal transport system for PAH was investigated only in kidney membrane vesicles [9,11] and not in the tubule in situ.…”